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Theory of Intelligent Design, the best explanation of Origins » Molecular biology of the cell » Metabolism » The Mitochondrion

The Mitochondrion

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1 The Mitochondrion on Fri Jul 31, 2015 8:05 pm

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THE MITOCHONDRION

http://reasonandscience.heavenforum.org/t2131-the-mitochondrion

Proteomic studies have revealed that mitochondria contain more than 1,000 different proteins, more than 99% of which are encoded by nuclear DNA. Thus, these proteins are synthesized as precursors on cytosolic ribosomes, specifically targeted to mitochondria and sorted into one of the four mitochondrial subcompartments. Various protein translocation machinery of the inner and outer mitochondrial membranes accomplish the complicated task of selective protein sorting into and across lipid bilayers. 2





James Villegas The mitochondria is an organelle (cellular organ) within a cell that takes organic sugar/ fuel molecules such as glucose (a product that results from digesting food) and converts said molecule(s) into an energy molecule known as ATP (Adenosine Triphosphate), which gives us the energy to do everyday physical tasks. In order to produce this molecule, a few basic steps must occur ( Glycolysis, Krebs Cycle/Citric Acid Cycle, and the Electron Transport Chain all in that order). The real money-maker that generates the majority of ATP is the last cycle, which is illustrated in the image of the electron transport chain (ETC) in the link above. This points to a Creator in that there are various protein complexes (such as ATP Synthase which is the ROTOR/ GEAR-LIKE structure in the end of the chain) and membranes IN THE ETC ALONE that are specifically designed to efficiently carry out a specific task. Often times, structures that are as efficient and complex as this are often existent due to the fact that they needed to be assembled. If the assemble of an intricate structure like this was left up to chance, the possibility of it being as efficient as it is now would be very low. This would be like asking a fully working engine to be assembled through random air currents blowing the pieces together, which although theoretically is not an impossibility, it is highly improbable. The same concept applies to this organic structure, although there is a possibility for a complex mechanism such as this to form independently isn't necessarily impossible, the probability of this doing so is HIGHLY UNLIKELY and thus needs to be intelligently designed if it is to work as efficiently as it does today.

The mitochondrion performs most cellular oxidations and produces the bulk of the animal cell’s ATP. A mitochondrion has two separate membranes: the outer membrane and the inner membrane. The inner membrane surrounds the innermost space (the matrix) of the mitochondrion and forms the cristae, which project into the matrix. The matrix and the inner membrane cristae are the major working parts of the mitochondrion. The membranes that form cristae account for a major part of the membrane surface area in most cells, and they contain the mitochondrion’s electron-transport chain (the respiratory chain). The mitochondrial matrix contains a large variety of enzymes, including those that convert pyruvate and fatty acids to acetyl CoA and those that oxidize this acetyl CoA to CO2 through the citric acid cycle. These oxidation reactions produce large amounts of NADH, whose high-energy electrons are passed to the respiratory chain. The respiratory chain then uses the energy derived from transporting electrons from NADH to molecular oxygen to pump H+ out of the matrix. This produces a large electrochemical proton gradient across the inner mitochondrial membrane, composed of contributions from both a membrane potential and a pH difference. This electrochemical gradient exerts a force to drive H+ back into the matrix. This proton- motive force is harnessed both to produce ATP and for the selective transport of metabolites across the inner mitochondrial membrane.

To maintain their high degree of organization in a universe that is constantly drifting toward chaos, cells have a constant need for a plentiful supply of ATP. In eukaryotic cells, most of the ATP that powers life processes is produced by specialized, membrane-enclosed, energy-converting organelles. These are of two types. Mitochondria, which occur in virtually all cells of animals, plants, and fungi, burn food molecules to produce ATP by oxidative phosphorylation. Chloroplasts, which occur only in plants and green algae, harness solar energy to produce ATP by photosynthesis. In electron micrographs, the most striking features of both mitochondria and chloroplasts are their extensive internal membrane systems. These internal membranes contain sets of membrane protein complexes that work together to produce most of the cell’s ATP. In bacteria, simpler versions of essentially the same protein complexes produce ATP, but they are located in the cell’s plasma membrane

chemiosmotic coupling, signifying a link between the chemical bond-forming reactions that generate ATP (“chemi”) and membrane transport processes (“osmotic”). The chemiosmotic process occurs in two linked stages, both of which are performed by protein complexes in a membrane.

Stage 1: High-energy electrons (derived from the oxidation of food molecules, from pigments excited by sunlight, or from other sources ) are transferred along a series of electron-transport protein complexes that form an electron-transport chain embedded in a membrane. Each electron transfer releases a small amount of energy that is used to
pump protons (H+) and thereby generate a large electrochemical gradient across the membrane. Such an electrochemical gradient provides a way of storing energy, and it can be
harnessed to do useful work when ions flow back across the membrane.

Stage 2: The protons flow back down their electrochemical gradient through an elaborate membrane protein machine called ATP synthase, which catalyzes the production of ATP from ADP and inorganic phosphate (Pi). This ubiquitous enzyme works like a turbine in the membrane, driven by protons, to synthesize ATP . In this way, the energy derived
from food or sunlight in stage 1 is converted into the chemical energy of a phosphate bond in ATP.

Electrons move through protein complexes in biological systems via tightly bound metal ions or other carriers that take up and release electrons easily, or by special small molecules that pick electrons up at one location and deliver them to another. For mitochondria, the first of these electron carriers is NAD+, a water-soluble small molecule that takes up two electrons and one H+ derived from food molecules (fats and carbohydrates) to become NADH. NADH transfers these electrons from the sites where the food molecules are degraded to the inner mitochondrial membrane. There, the electrons from the energy-rich NADH are passed from one membrane protein complex to the next, passing to a lower-energy compound at each step, until they reach a final complex in which they combine with molecular oxygen (O2) to produce water. The energy released at each step as the electrons flow down this path from the energy-rich NADH to the low-energy water molecule drives H+ pumps in the inner mitochondrial membrane, utilizing three
different membrane protein complexes. Together, these complexes generate the proton-motive force harnessed by ATP synthase to produce the ATP that serves as the universal energy currency throughout the cell.



Electron-transport processes In the mitochondrion, fats and carbohydrates from food molecules are fed into the citric acid cycle and provide electrons to generate the energy-rich compound NADH from NAD+. These electrons then flow down an energy gradient as they pass from one complex to the next in the electron-transport chain, until they combine with molecular O2 in the last complex to produce water. The energy released at each stage is harnessed to pump H+ across the membrane.

Mitochondria occupy up to 20% of the cytoplasmic volume of a eukaryotic cell. Although they are often depicted as short, bacterium-like bodies with a diameter of 0.5–1 μm, they are in fact remarkably dynamic and plastic, moving about the cell, constantly changing shape, dividing, and fusing. Mitochondria are often associated with the microtubular cytoskeleton, which determines their orientation and distribution in different cell types. Thus, in highly polarized cells such as neurons, mitochondria can move long distances (up to a meter or more in the extended axons of neurons), being propelled along the tracks of the microtubular cytoskeleton. In other cells, mitochondria remain fixed at points of high energy demand; for example, in skeletal or cardiac muscle cells, they pack between myofibrils, and in sperm cells they wrap tightly around the flagellum.  Mitochondria also interact with other membrane systems in the cell, most notably the endoplasmic reticulum (ER). Contacts between mitochondria and ER define specialized domains thought to facilitate the exchange of lipids between the two membrane systems. These contacts also appear to induce mitochondrial fission, which  is involved in the distribution and partitioning of mitochondria within cells. Mitochondria is a prerequisite for  complex animals. Without mitochondria, present-day animal cells would have had to generate all of their ATP through anaerobic glycolysis. When Glycolysis converts glucose to pyruvate, it releases only a small fraction of the total free energy that is potentially available from glucose oxidation . In mitochondria, the metabolism of sugars is complete: pyruvate is imported into the mitochondrion and ultimately oxidized by O2 to CO2 and H2O, which allows 15 times more ATP to be made from a sugar than by glycolysis alone. This became possible only when enough molecular oxygen accumulated in the Earth’s atmosphere to allow organisms to take full advantage, via respiration, of the large amounts of energy potentially available from the oxidation of organic compounds. Mitochondria are large enough to be seen in the light microscope.

Where the inner membrane runs parallel to the outer membrane, between the cristae, it is known as the inner boundary membrane. The narrow (20–30 nm) gap between the inner boundary membrane and the outer membrane is known as the intermembrane space. The cristae are about 20 nm-wide membrane discs or tubules that protrude deeply into the matrix and enclose the crista space. The crista membrane is continuous with the inner boundary membrane, and where their membranes join, the membrane forms narrow membrane tubes or slits, known as crista junctions. Like the bacterial outer membrane, the outer mitochondrial membrane is freely permeable to ions and to small molecules as large as 5000 daltons. This is because it contains many porin molecules, a special class of β-barrel-type membrane protein that creates aqueous pores across the membrane. As a consequence, the intermembrane space between the outer and inner membrane has the same pH and ionic composition as the cytoplasm, and there is no electrochemical gradient across the outer membrane.

The Mitochondrion Has an Outer Membrane and an Inner Membrane

Mitochondria have an outer and an inner membrane. The two membranes have distinct functions and properties and delineate separate compartments within the organelle. The inner membrane, which surrounds the internal mitochondrial matrix compartment is highly folded to form invaginations known as cristae (the singular is crista), which contain in their membranes the proteins of the electron-transport chain.



Picture above: Structure of a mitochondrion. (A)  The outer membrane envelops the inner boundary membrane. The inner membrane is highly folded into tubular or lamellar cristae, which crisscross the matrix. The dense matrix, which contains most of the mitochondrial protein, appears dark in the electron microscope, whereas the intermembrane space and the crista space appear light due to their lower protein content. The inner boundary membrane follows the outer membrane closely at a distance of ≈20 nm. The inner membrane turns sharply at the cristae junctions, where the cristae join the inner boundary membrane. (C) Schematic drawing of a mitochondrion showing the outer membrane (gray), and the inner membrane (yellow). Note that the inner membrane is compartmentalized into the inner boundary membrane and the crista membrane. There are three distinct spaces: the inner membrane space, the crista space, and the matrix.

The matrix contains the genetic system of the mitochondrion, including the mitochondrial DNA and the ribosomes. The mitochondrial DNA  is organized into compact bodies—the nucleoids—by special scaffolding proteins that also function as transcription regulatory proteins. The large number of enzymes required for the maintenance of the mitochondrial
genetic system, as well as for many other essential reactions to be outlined next, accounts for the very high protein concentration in the matrix; at more than 500 mg/mL, this concentration is close to that in a protein crystal.

Mitochondria Have Many Essential Roles in Cellular Metabolism

Mitochondria not only generate most of the cell’s ATP; they also provide many other essential resources for biosynthesis and cell growth. Before describing in detail the remarkable machinery of the respiratory chain, we diverge briefly to touch on some of these important roles. Mitochondria are critical for buffering the redox potential in the cytosol. Cellsneed a constant supply of the electron acceptor NAD+ for the central reaction in glycolysis that converts glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate. This NAD+ is converted to NADH in the process, and the NAD+ needs to be regenerated by transferring the high-energy NADH electrons somewhere. The NADH electrons will eventually be used to help drive oxidative phosphorylation inside the mitochondrion. But the inner mitochondrial membrane is impermeable to NADH. The electrons are therefore passed from the NADH to smaller molecules in the cytosol that can move through the inner mitochondrial membrane. Once in the matrix, these smaller molecules transfer their electrons to NAD+ to form mitochondrial NADH, after which they are returned to the cytosol for recharging—creating a so-called shuttle system for the NADH electrons. In addition to ATP, biosynthesis in the cytosol requires both a constant supply of reducing power in the form of NADPH and small carbon-rich molecules to serve as building blocks. Descriptions of biosynthesis often state that the needed carbon skeletons come directly from the breakdown of sugars, whereas the NADPH is produced in the cytosol by a side pathway for the breakdown of sugars (the pentose phosphate pathway, an alternative to glycolysis). But under conditions where nutrients abound and plenty of ATP is available, mitochondria help to generate both the reducing power and the carbon- rich building blocks  needed for cell growth. For this purpose, excess citrate produced in the mitochondrial matrix by the citric acid cycle is transported down its electrochemical gradient to the cytosol, where it is metabolized to produce essential components of the cell. Thus, for example, as part of a cell’s response to growth signals, large amounts of acetyl CoA are produced in the cytosol from citrate exported from mitochondria, accelerating the production of the fatty acids
and sterols that build new membranes .

The urea cycle is a central metabolic pathway in mammals that converts the ammonia (NH4 +) produced by the breakdown of nitrogen-containing compounds (such as amino acids) to the urea excreted in urine. Two critical steps of the urea cycle are carried out in the mitochondria of liver cells, while the remaining steps occur in the cytosol. Mitochondria also play an essential part in the metabolic adaptation of cells to different nutritional conditions. For example, under conditions of starvation, proteins in our bodies are broken down to amino acids, and the amino acids are imported into mitochondria and oxidized to produce NADH for ATP production. The biosynthesis of heme groups—which, as we shall see in the next section, play a central part in electron transfer—is another critical process that is shared between the mitochondrion and the cytoplasm. Iron–sulfur clusters, which are essential not only for electron transfer in the respiratory chain, but also for the maintenance and stability of the nuclear genome, are produced in mitochondria (and chloroplasts). Nuclear genome instability, a hallmark of cancer, can sometimes be linked to the decreased function of cellular proteins that contain iron–sulfur clusters. Mitochondria also have a central role in membrane biosynthesis. Cardiolipin is a two-headed phospholipid that is confined to the inner mitochondrial membrane, where it is also produced. But mitochondria are also a major source of phospholipids for the biogenesis of other cell membranes. Phosphatidylethanolamine, phosphatidylglycerol, and phosphatidic acid are synthesized in the mitochondrion, while phosphatidylinositol, phosphatidylcholine, and phosphatidylserine are primarily synthesized in the endoplasmic reticulum (ER). Most of the cell’s membranes are assembled in the ER. The exchange of lipids between the ER and mitochondria is thought to occur at special sites of close contact by an as-yet unknown mechanism. Finally, mitochondria are important calcium buffers, taking up calcium from the ER and sarcoplasmic reticulum at special membrane junctions. Cellular calcium levels control muscle contraction  and alterations are implicated in neurodegeneration and apoptosis. Clearly, cells and organisms depend on mitochondria in many different ways. We now return to the central function of the mitochondrion in respiratory ATP generation.

The Inner Membrane Cristae Contain the Machinery for Electron Transport and ATP Synthesis

Unlike the outer mitochondrial membrane, the inner mitochondrial membrane is a diffusion barrier to ions and small molecules, just like the bacterial inner membrane. However, selected ions, most notably protons and phosphate, as well as essential metabolites such as ATP and ADP, can pass through it by means of special transport proteins. The inner mitochondrial membrane is highly differentiated into functionally distinct regions with different protein compositions.  The lateral segregation of membrane regions with different protein and lipid compositions is a key feature of cells. In the inner mitochondrial membrane, the boundary membrane region is thought to contain the machinery for protein import, new membrane insertion, and assembly of the respiratory-chain complexes. The membranes of the cristae, which are continuous with the boundary membrane, contain the ATP synthase enzyme that produces most of the cell’s ATP; they also contain the large protein complexes of the respiratory chain—the name given to the mitochondrion’s electron-transport chain. At the cristae junctions, where the membranes of the cristae join the boundary membrane, special protein complexes provide a diffusion barrier that segregates the membrane proteins in the two regions of the inner membrane; these complexes are also thought to anchor the cristae to the outer membrane, thus maintaining the highly folded topology of the inner membrane. Cristae membranes have one of the highest protein densities of all biological membranes, with a lipid content of 25% and a protein content of 75% by weight. The folding of the inner membrane into cristae greatly increases the membrane area available for oxidative phosphorylation. In highly active cardiac muscle cells, for example, the total area of cristae membranes can be up to 20 times larger than the area of the cell’s plasma membrane. In total, the surface area of cristae membranes in each human body adds up to roughly the size of a football field.

The Citric Acid Cycle in the Matrix Produces NADH

Together with the cristae that project into it, the matrix is the major working part of the mitochondrion. Mitochondria can use both pyruvate and fatty acids as fuel. Pyruvate is derived from glucose and other sugars, whereas fatty acids are derived from fats. Both of these fuel molecules are transported across the inner mitochondrial membrane by specialized transport proteins, and they are then converted to the crucial metabolic intermediate acetyl-CoA by enzymes located in the mitochondrial matrix.

The acetyl groups in acetyl-CoA are oxidized in the matrix via the citric acid cycle, also called the Krebs cycle. The oxidation of these carbon atoms in acetyl CoA produces CO2, which diffuses out of the mitochondrion to be released to the environment as a waste product. More importantly, the citric acid cycle saves a great deal of the bond energy released by this oxidation in the form of electrons carried by NADH. This NADH transfers its electrons from the matrix to the electron-transport chain in the inner mitochondrial
membrane, where—through the chemiosmotic coupling process the energy that was carried by NADH electrons is converted into phosphate-bond energy in ATP.



Picture above: A summary of the energy converting metabolism in mitochondria. Pyruvate and fatty acids enter the mitochondrion (top of the figure) and are broken down to acetyl CoA. The acetyl-CoA is metabolized by the citric acid cycle, which reduces NAD+ to NADH, which then passes its high-energy electrons to the first complex in the electron-transport chain. In the process of oxidative phosphorylation, these electrons pass along the electron transport chain in the inner membrane cristae to oxygen (O2). This electron transport generates a proton gradient, which drives the production of ATP by the ATP synthase. Electrons from the oxidation of succinate, a reaction intermediate in the  citric acid cycle, take a separate path to enter this electron-transport chain The membranes that comprise the mitochondrial inner membrane—the inner boundary membrane and the crista membrane—contain different mixtures of proteins and they are therefore shaded differently in this diagram.

A Chemiosmotic Process Couples Oxidation Energy to ATP Production

Although the citric acid cycle that takes place in the mitochondrial matrix is considered to be part of aerobic metabolism, it does not itself use oxygen. Only the final step of oxidative metabolism consumes molecular oxygen (O2) directly. Nearly all the energy available from metabolizing carbohydrates, fats, and other foodstuffs in earlier stages is saved in the form of energy-rich compounds that feed electrons into the respiratory chain in the inner mitochondrial membrane. These electrons, most of which are carried by NADH, finally combine with O2 at the end of the respiratory chain to form water. The energy released during the complex series of electron transfers from NADH to O2 is harnessed in the inner membrane to generate an electrochemical gradient that drives the conversion of ADP + Pi to ATP. For this reason, the term oxidative phosphorylation is
used to describe this final series of reactions.



The total amount of energy released by biological oxidation in the respiratory chain is equivalent to that released by the explosive combustion of hydrogen when it combines with oxygen in a single step to form water. But the combustion of hydrogen in a single-step chemical reaction, which has a strongly negative ΔG, releases this large amount of energy unproductively as heat. In the respiratory chain, the same energetically favorable reaction H2 + ½ O2 → H2O is divided into small steps.



This stepwise process allows the cell to store nearly half of the total energy that is released in a useful form. At each step, the electrons, which can be thought of as having been removed from a hydrogen molecule to produce two protons, pass through a series of electron carriers in the inner mitochondrial membrane. At each of three distinct steps along the way (marked by the three electron-transport complexes of the respiratory chain), much of the energy is utilized for pumping protons across the membrane. At the end of the
electron-transport chain, the electrons and protons recombine with molecular oxygen into water. Water is a very low-energy molecule and is thus very stable; it can serve as anelectron donor only when a large amount of energy from an external source is spent on splitting it into protons, electrons, and molecular oxygen. This is exactly what happens in oxygenic photosynthesis, where the external energy source is the sun. 

The Energy Derived from Oxidation Is Stored as an Electrochemical Gradient

In mitochondria, the process of electron transport begins when two electrons and a proton are removed from NADH (to regenerate NAD+). These electrons are passed to the first of about 20 different electron carriers in the respiratory chain. The electrons start at a large negative redox potential —that is, at a high energy level—which gradually drops as they pass along the chain. The proteins involved are grouped into three large respiratory enzyme complexes, each composed of protein subunits that sit in the inner mitochondrial membrane. Each complex in the chain has a higher affinity for electrons than its predecessor, and electrons pass sequentially from one complex to the next until they are finally
transferred to molecular oxygen, which has the highest electron affinity of all. The net result is the pumping of H+ out of the matrix across the inner membrane, driven by the energetically favorable flow of electrons. This transmembrane movement of H+ has two major consequences:

1. It generates a pH gradient across the inner mitochondrial membrane, with a high pH in the matrix (close to)  and a lower pH in the intermembrane space. Since ions and small molecules equilibrate freely across the outer mitochondrial membrane, the pH in the intermembrane space is the same as in the cytosol (generally around pH 7.4).

2. It generates a voltage gradient across the inner mitochondrial membrane, creating a membrane potential with the matrix side negative and the crista space side positive. The pH gradient (ΔpH) reinforces the effect of the membrane potential (ΔV ), because the latter acts to attract any positive ion into the matrix and to push any negative ion out. Together, ΔpH and ΔV make up the electrochemical gradient, which is measured in units of millivolts (mV). This gradient exerts a protonmotive force, which tends to drive H+ back into the matrix (Figure below )



1) http://www.sciencedirect.com/science/article/pii/S0167488912001449
2) https://www.biochemie.uni-freiburg.de/ag/vanderLaan/research?set_language=en



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2 THE PROTON PUMPS OF THE ELECTRONTRANSPORTCHAIN on Tue Aug 04, 2015 12:03 am

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THE PROTON PUMPS OF THE ELECTRONTRANSPORTCHAIN

Having considered in general terms how a mitochondrion uses electron transport to generate a proton-motive force, we now turn to the molecular mechanisms that underlie this membrane-based energy-conversion process. In describing the respiratory chain of mitochondria, we accomplish the larger purpose of explaining how an electron-transport process can pump protons across a membrane. As stated at the beginning of this chapter, mitochondria, chloroplasts, archaea, and bacteria use very similar chemiosmotic mechanisms. In fact, these mechanisms underlie the function of all living organisms—including anaerobes that derive all their energy from electron transfers between two inorganic molecules. We start with some of the basic principles on which all of these processes depend.

The Redox Potential Is a Measure of Electron Affinities

In chemical reactions, any electrons removed from one molecule are always passed to another, so that whenever one molecule is oxidized, another is reduced. As with any other chemical reaction, the tendency of such redox reactions to proceed spontaneously depends on the free-energy change (ΔG) for the electron transfer, which in turn depends on the relative affinities of the two molecules for electrons. Because electron transfers provide most of the energy for life, it is worth taking the time to understand them.  Acids donate protons and bases accept them. Acids and bases exist in conjugate acid–base pairs, in which the acid is readily converted into the base by the loss of a proton. For example, acetic acid (CH3COOH) is converted into its conjugate base, the acetate ion (CH3COO–), in the reaction: CH3COOH CH3COO– + H+. In an exactly analogous way, pairs of compounds such as NADH and NAD+ are called redox pairs, since NADH is converted to NAD+ by the loss of electrons in the reaction: NADH NAD+ + H+ + 2e– NADH is a strong electron donor: because two of its electrons are engaged in a covalent bond which releases energy when broken, the free-energy change for passing these electrons to many other molecules is favorable. Energy is required to form this bond from NAD+, two electrons, and a proton (the same amount of energy that was released when the bond was broken). Therefore NAD+, the redox partner of NADH, is of necessity a weak electron acceptor. We can measure the tendency to transfer electrons from any redox pair experimentally.
All that is required is the formation of an electrical circuit linking a 1:1 (equimolar) mixture of the redox pair to a second redox pair that has been arbitrarily selected as a reference standard, so that we can measure the voltage difference between them (Panel 14–1). This voltage difference is defined as the redox potential; electrons move spontaneously from a redox pair like NADH/NAD+ with a lower redox potential (a lower affinity for electrons) to a redox pair like O2/H2O with a higher redox potential (a higher affinity for electrons). Thus, NADH is a good molecule for donating electrons to the respiratory chain, while O2 is well suited to act as the “sink” for electrons at the end of the chain. The difference in redox potential, ΔEʹ0, is a direct measure of the standard free-energy change (ΔG°) for the transfer of an electron from one molecule to another.

In the mitochondrial electron-transport chain, six different cytochrome hemes, eight iron–sulfur clusters, three copper atoms, a flavin mononucleotide (another electron-transfer cofactor), and ubiquinone work in a defined sequence to carry electrons from NADH to O2. In total, this pathway involves more than 60 different polypeptides arranged in three large membrane protein complexes, each of which binds several of the above electron-carrying cofactors. 







As we would expect, the electron-transfer cofactors have increasing affinities for electrons (higher redox potentials) as the electrons move along the respiratory chain. The redox potentials have been fine-tuned  by the protein environment of each cofactor, which alters the cofactor’s normal affinity for electrons. Because iron–sulfur clusters have a relatively low affinity for electrons, they predominate in the first half of the respiratory chain; in contrast, the heme cytochromes predominate further down the chain, where a higher electron affinity is required.

Electron Transfers Release Large Amounts of Energy

Those pairs of compounds that have the most negative redox potentials have the weakest affinity for electrons and therefore are useful as carriers with a strong tendency to donate electrons. Conversely, those pairs that have the most positive redox potentials have the greatest affinity for electrons and therefore are useful as carriers with a strong tendency to accept electrons. A 1:1 mixture of NADH and NAD+ has a redox potential of –320 mV, indicating that NADH has a strong tendency to donate electrons; a 1:1 mixture of H2O and ½O2 has a redox potential of +820 mV, indicating that O2 has a strong tendency to accept electrons. The difference in redox potential is 1140 mV, which means that
the transfer of each electron from NADH to O2 under these standard conditions is enormously favorable, since ΔG° = –109 kJ/mole, and twice this amount of energy is gained for the two electrons transferred per NADH molecule. If we compare this free-energy change with that for the formation of the phosphoanhydride bonds in ATP, where ΔG° = 30.6 kJ/mole (see Figure 2–50), we see that, under standard conditions, the oxidation of one NADH molecule releases more than enough energy to synthesize seven molecules of ATP from ADP and Pi. (In the cell, the number of ATP molecules generated will be lower because the standard conditions are far from the physiological ones; in addition, small amounts of energy are inevitably dissipated as heat along the way.)

Transition Metal Ions and Quinones Accept and Release Electrons Readily

The electron-transport properties of the membrane protein complexes in the respiratory chain depend upon electron-carrying cofactors, most of which are transition metals such as Fe, Cu, Ni, and Mn, bound to proteins in the complexes. These metals have special properties that allow them to promote both enzyme catalysis and electron-transfer reactions. Most relevant here is the fact that their ions exist in several different oxidation states with closely spaced redox potentials, which enables them to accept or give up electrons readily; this property is exploited by the membrane protein complexes in the respiratory chain to move electrons both within and between complexes.

The simplest of the electron-transfer cofactors in the respiratory chain—and the only one that is not always bound to a protein—is a quinone (called ubiquinone, or coenzyme Q). A quinone (Q) is a small hydrophobic molecule that is freely mobile in the lipid bilayer. This electron carrier can accept or donate either one or two electrons. Upon reduction (note that reduced quinones are called quinols), it picks up a proton from water along with each electron into artificial lipid bilayer vesicles and shown to pump protons across the membrane as electrons pass through them.



Quinone electron carriers. Ubiquinone in the lipid bilayer picks up one H+ (red) from the aqueous environment for each electron (blue) it accepts, in two steps, from respiratorychain complexes. The first step involves the acquisition of a proton and an electron and converts the ubiquinone into an unstable ubisemiquinone radical. In the second step, it becomes a fully reduced ubiquinone (called ubiquinol), which is freely mobile as an electron carrier in the lipid bilayer of the membrane. When the ubiquinol donates its electrons to the next complex in the chain, the two protons are released. The long hydrophobic tail (green) that confines ubiquinone to the membrane consists of 6–10 five-carbon isoprene units, depending on the organism. The corresponding electron carrier in the photosynthetic membranes of chloroplasts is plastoquinone, which has almost the
same structure and works in the same way. For simplicity, we refer to both ubiquinone and plastoquinone  as quinone (abbreviated as Q).


In the mitochondrion, the three complexes are linked in series, serving as electron- transport-driven H+ pumps that pump protons out of the matrix to acidify the crista space



The path of electrons through the three respiratory-chain proton pumps. The approximate size and shape of each complex is shown. During the transfer of electrons from NADH to oxygen (blue arrows), ubiquinone and cytochrome c serve as mobile carriers that ferry electrons from one complex to the next. During the electron-transfer reactions, protons are pumped across the membrane by each of the respiratory enzyme complexes, as indicated (red arrows). For historical reasons, the three proton pumps in the respiratory chain are sometimes denoted as Complex I, Complex III, and Complex IV, according to the order in which electrons pass through them from NADH. Electrons from the oxidation of succinate by succinate dehydrogenase (designated as Complex II) are fed into the electron-transport chain in the form of reduced ubiquinone. Although embedded in the crista membrane, succinate dehydrogenase does not pump protons and thus does not contribute to the proton-motive force; it is therefore not considered to be an integral part of the respiratory chain.

1. The NADH dehydrogenase complex (often referred to as Complex I) is the largest of these respiratory enzyme complexes. It accepts electrons from NADH and passes them through a flavin mononucleotide and eight iron–sulfur clusters to the lipid-soluble electron carrier ubiquinone. The reduced ubiquinol then transfers its electrons to cytochrome c reductase.

2. The cytochrome c reductase (also called the cytochrome b-c1 complex) is a large membrane protein assembly that functions as a dimer. Each monomer contains three cytochrome hemes and an iron–sulfur cluster. The complex accepts electrons from ubiquinol and passes them on to the small, soluble protein cytochrome c, which is located in the crista space and carries electrons one at a time to cytochrome c oxidase.

3. The cytochrome c oxidase complex contains two cytochrome hemes and three copper atoms. The complex accepts electrons one at a time from cytochrome c and passes them to molecular oxygen. In total, four electrons and four protons are needed to convert one molecule of oxygen to water. We have previously discussed how the redox potential reflects electron affinities.



Redox potential changes along the mitochondrial electrontransport chain. The redox potential (designated Eʹ0) increases as electrons flow down the respiratory chain to oxygen. The standard free-energy change in kilojoules, ΔG°, for the transfer of each of the two electrons donated by an NADH molecule can be obtained from the left-hand
ordinate [ΔG° = –n(0.096) ΔEʹ0, where n is the number of electrons transferred across a redox potential change of ΔEʹ0 mV]. Electrons flow through a respiratory enzyme complex by passing in sequence through the multiple electron carriers in each complex (blue arrows). As indicated, part of the favorable free-energy change is harnessed by each enzyme complex to pump H+ across the inner mitochondrial membrane (red arrows). The NADH dehydrogenase pumps up to four H+ per electron, the cytochrome c reductase complex pumps two, whereas the cytochrome c oxidase complex pumps one per electron.


The figure above presents an outline of the redox potentials measured along the respiratory chain. These potentials change in three large steps, one across each proton translocating respiratory complex. The change in redox potential between any two electron carriers is directly proportional to the free energy released when an electron transfers between them. Each complex acts as an energy-conversion device by harnessing some of this free-energy change to pump H+ across the inner membrane, thereby creating an electrochemical proton gradient as electrons pass along the chain.



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3 Re: The Mitochondrion on Wed Aug 05, 2015 2:12 pm

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ATP PRODUCTION IN MITOCHONDRIA

As we have just discussed, the three proton pumps of the respiratory chain each contribute to the formation of an electrochemical proton gradient across the inner mitochondrial membrane. This gradient drives ATP synthesis by ATP synthase, a large membrane-bound protein complex that performs the extraordinary feat of converting the energy contained in this electrochemical gradient into biologically useful, chemical-bond energy in the form of ATP (see Figure 14–10). Protons flow down their electrochemical gradient through the membrane part of this proton turbine, thereby driving the synthesis of ATP from ADP and Pi in the extramembranous part of the complex. As discussed in Chapter 2, the formation of ATP from ADP and inorganic phosphate is highly unfavorable energetically. As we shall see, ATP synthase can produce ATP only because of allosteric shape changes in this protein complex that directly couple ATP synthesis to the energetically favorable flow of protons across its membrane. The Large Negative Value of ΔG for ATP Hydrolysis Makes ATP Useful to the Cell. An average person turns over roughly 50 kg of ATP per day. In athletes running a marathon, this figure can go up to several hundred kilograms. The ATP produced in mitochondria is derived from the energy available in the intermediates NADH, FADH2, and GTP. These three energy-rich compounds are produced both by the oxidation of glucose, and by the oxidation of fats . Glycolysis alone can produce only two molecules of ATP for every molecule of glucose that is metabolized, and this is the total energy yield for the fermentation processes that occur in the absence of O2 .


In oxidative phosphorylation, each pair of electrons donated by the NADH produced in mitochondria can provide energy for the formation of about 2.5 molecules of ATP. Oxidative
phosphorylation also produces 1.5 ATP molecules per electron pair from the FADH2 produced by succinate dehydrogenase in the mitochondrial matrix, and from the NADH molecules produced by glycolysis in the cytosol. From the product yields of glycolysis and the citric acid cycle, we can calculate that the complete oxidation of one molecule of glucose—starting with glycolysis and ending with oxidative phosphorylation—gives a net yield of about 30 molecules of ATP. Nearly all this ATP is produced by the mitochondrial ATP synthase.

ATP PRODUCTION IN MITOCHONDRIA

The three proton pumps of the respiratory chain each contribute to the formation of an electrochemical proton gradient across the inner mitochondrial membrane. This gradient drives ATP synthesis by ATP synthase, a large membrane-bound protein complex that performs the extraordinary feat of converting the energy contained in this electrochemical gradient into biologically useful, chemical-bond energy in the form of ATP . Protons flow down their electrochemical gradient through the membrane part of this proton turbine, thereby driving the synthesis of ATP from ADP and Pi in the extramembranous part of the complex. The formation of ATP from ADP and inorganic phosphate is highly unfavorable energetically. As we shall see, ATP synthase can produce ATP only because of allosteric shape changes in this protein complex that directly couple ATP synthesis to the energetically favorable flow of protons across its membrane.


Mitochondria,small bodies in the cytoplasm, enclosed by a double layer of membrane, take up oxygen and harness energy from the oxidation of food molecules—such as sugars—
to produce most of the ATP that powers the cell’s activities. Mitochondria are similar in size to small bacteria, and, like bacteria, they have their own genome in the form of a circular DNA molecule, their own ribosomes that differ from those elsewhere in the eukaryotic cell, and their own transfer RNAs.

It is now generally accepted that mitochondria originated from free-living oxygen-metabolizing (aerobic) bacteria that were engulfed by an ancestral cell that could otherwise make no such use of oxygen (that is, was anaerobic). Escaping digestion, these bacteria evolved in symbiosis with the engulfing cell and its progeny, receiving shelter and nourishment in return for the power generation they performed for their hosts. This partnership between a primitive anaerobic predator cell and an aerobic bacterial cell is thought to have been established about 1.5 billion years ago, when the Earth’s atmosphere first became rich in oxygen

The Energy Derived from Oxidation Is Stored as an Electrochemical Gradient

Mitochondria are ubiquitous organelles surrounded by two membranes, the outer and the inner membrane, which confine two aqueous compartments, the matrix and the intermembrane space (IMS). Tubular invaginations of the inner mitochondrial membrane form the cristae, which harbor the enzyme complexes of the oxidative phosphorylation system. In addition to their central role in ATP synthesis mitochondria accommodate central metabolic pathways, like the Krebs cycle and the β-oxidation of fatty acids. They provide cells with a large number of metabolites, such as amino acids and steroids, and are involved in the formation of heme and iron-sulfur clusters. Based on proteomic analyses it has been estimated that mitochondria contain ~ 1500 different proteins in mammals and ~ 1000 different proteins in yeast 1

Complex organelles, mitochondria (singular = mitochondrion) have several important functions in eukaryotic cells. Their unique membranes are used to generate ATP, greatly increasing the energy yield from the breakdown of carbohydrates and lipids. Mitochondria can self replicate and also contain their own DNA. Owing to these properties, mitochondria are believed to have bacterial origins. The very survival of individual cells depends on the integrity of their mitochondria. Programmed cell death or apoptosis occurs when pores are formed in the mitochondrial membrane allowing for the release of proteins that facilitate the apoptotic death process . The unique structure of mitochondria is important in allowing them to perform these necessary cellular functions.

A. Function in energy production

One characteristic feature of mitochondria is the double phospholipid bilayer membranes that form the outer boundary of the organelle. The inner mitochondrial membrane forms folded structures called cristae that protrude into the mitochondrial lumen (space) known as the mitochondrial matrix. Protons (H+) are pumped out of the mitochondrial matrix, creating an electrochemical gradient of protons. The fl ow of protons back into the matrix drives the formation of ATP from carbohydrates and lipids in the process of oxidative phosphorylation. The presence of mitochondria within a cell enhances the amount of ATP produced from each glucose molecule that is broken down, as evidenced by human red blood cells that lack mitochondria. In red blood cells, only 2 ATP molecules are generated per glucose molecule. In contrast, in human cells with mitochondria, the yield of ATP is as high as 32 per glucose molecule.

B. Role as independent units within the eukaryotic cells

Mitochondria also contain DNA (mtDNA) and ribosomes for the production of RNA and some mitochondrial proteins. mtDNA is approximately 1% of total cellular DNA and exists in a circular arrangement within the mitochondrial matrix. Mutations or errors in some mitochondrial genes can result in disease. Most mitochondrial proteins, however, are encoded by the genomic DNA of the cell’s nucleus. Mitochondria self replicate or divide by fi ssion, as do bacteria. Mitochondria are actually believed to have arisen from bacteria that were
engulfed by ancestral eukaryotic cells.

C. Function in cell survival

Survival of eukaryotic cells depends on intact mitochondria. At times, the death of an individual cell is important for the benefi t of the organism. During development, some cells must die to allow for proper tissue and organ formation. Death of abnormal cells, such as virally infected cells or cancerous cells, is also for the good of the organism. In all these cases, mitochondrial involvement is important to ensure cell survival when it is appropriate and also to facilitate programmed cell death when necessary. When the process of programmed cell death or apoptosis is stimulated in a cell, proapoptotic proteins insert into the mitochondrial membrane, forming pores. A protein known as cytochrome c can then leave the intermembrane space of the mitochondria through the pores, entering the cytosol



Cytochrome c in the cytosol stimulates a cascade of biochemical events resulting in apoptotic death of the cell

Mitochondria: master regulators of danger signalling  1

Throughout more than 1.5 billion years of obligate endosymbiotic co-evolution, mitochondria have developed not only the capacity to control distinct molecular cascades leading to cell death but also the ability to sense (and react to) multiple situations of cellular stress, including viral infection. In addition, mitochondria can emit danger signals that alert the cell or the whole organism of perturbations in homeostasis, hence promoting the induction of cell-intrinsic or systemic adaptive responses, respectively. As such, mitochondria can be considered as master regulators of danger signalling.

1) http://www.nature.com/nrm/journal/v13/n12/full/nrm3479.html

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Organization of the mitochondrial translation machinery 2

Mitochondria are produced from the transcription and translation of genes both in the nuclear genome and in the mitochondrial genome. 1
Mitochondrial DNA (mtDNA or mDNA) is the DNA located in mitochondria
The genes for some of them, if not most, are thought to have originally been of bacterial origin, having since been transferred to the eukaryotic nucleus during evolution.

Why and how that could and should have happened, is the big question....

Mitochondrial DNA is replicated by the DNA polymerase gamma complex  3
The replisome machinery is formed by DNA polymerase, TWINKLE and mitochondrial SSB proteins. TWINKLE is a helicase, which unwinds short stretches of dsDNA in the 5′ to 3′ direction

TWINKLE is an essential mitochondrial helicase required for synthesis of nascent D-loop strands and complete mtDNA replication 4

Replication of the mammalian mitochondrial DNA (mtDNA) is dependent on the minimal replisome, consisting of the

heterotrimeric mtDNA polymerase (POLG),
the hexameric DNA helicase TWINKLE
the tetrameric single-stranded DNA-binding protein (mtSSB)


Conditional knockout of Twinkle results in severe and rapid mtDNA depletion in heart and skeletal muscle. No replication intermediates or deleted mtDNA molecules are observed after Twinkle knockout, suggesting that TWINKLE once loaded is very processive. We also demonstrate that TWINKLE is essential for nascent H-strand synthesis in the D-loop, thus showing that there is no separate DNA helicase responsible for replication of this region. Our data thus suggest that the relative levels of abortive D-loop synthesis versus complete mtDNA replication are regulated and may provide a mechanism to control progression to complete mtDNA replication.

Mammalian mtDNA only encodes 13 proteins, but these are nevertheless essential for cell viability as they are crucial components of the oxidative phosphorylation system, located in the inner mitochondrial membrane

All of the proteins required for mtDNA maintenance and expression are encoded by the nuclear genome and have to be imported into mitochondria after synthesis in the cytosol. Therefore, it is clear that a coordinated action between the two cellular genomes is required to regulate oxidative phosphorylation capacity in response to physiological demand and disease states

That makes it pretty clear, that is a interdependent and interlocked system, so one more clear evidence that the endosymbiosis theory is nonsense. It makes it also clear, that both, the nucleus, all of the proteins required for mtDNA maintenance and expression, the DNA that encodes for these proteins, the import machinery, the cytosol, the cell membrane, and mitochondria had to emerge at the same time. A stepwise evolutionary and gradual emergence  is impossible.



(a) Isolated mitochondria were labelled for 10 min with radioactive ​methionine and synthesized proteins were visualized by SDS–PAGE and autoradiography. The synthesized translation products are indicated. m​Cox2 indicates mature processed ​Cox2. (b) Rendered and segmented version of a tomogram depicting the outer (grey) and inner mitochondrial membrane (yellow) detected mitoribosomes visualized by the template (blue) and a subset of ATP synthases (red). Mitoribosomes and ATP synthases can be readily discerned in mildly Gaussian-filtered (1.5 nm width) slices of the tomogram (boxed areas). (c) Distribution of shortest distances between the centre of mass of detected mitoribosomes and the inner mitochondrial membrane represented as histogram and box-whisker plot for 478 mitoribosomes from three tomograms. The box includes the median, upper and lower quartiles of the distribution. Box whiskers include 80% of the data to indicate variability outside the upper and lower quartiles. The dashed line corresponds to the approximate radius of a mitoribosome (14 nm).

Whereas the structure and function of cytosolic ribosomes have been studied in great detail, we know surprisingly little about the structural basis of mitochondrial protein synthesis. Most mitoribosomes reside in immediate proximity to the inner mitochondrial membrane, in line with their specialization in the synthesis of hydrophobic membrane proteins.


1) https://en.wikipedia.org/wiki/Mitochondrial_biogenesis
2) http://www.nature.com/ncomms/2015/150122/ncomms7019/full/ncomms7019.html
3) https://en.wikipedia.org/wiki/Mitochondrial_DNA
4) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633371/



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5 Re: The Mitochondrion on Tue Aug 11, 2015 5:16 pm

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Mitochondrial membrane biogenesis: phospholipids and proteins go hand in hand 1

Mitochondrial membrane biogenesis requires the import and synthesis of proteins as well as phospholipids.The biochemical approach of Kutik et al. (2008) uncovered an unexpected role of the mitochondrial translocator assembly and maintenance protein, Tam41, in the biosynthesis of cardiolipin (CL), the signature phospholipid of mitochondria. The genetic analyses of Osman et al. (2009) led to the discovery of a new class of mitochondrial proteins that coordinately regulate CL and phosphatidylethanolamine, another key mitochondrial phospholipid. These elegant studies highlight overlapping functions and interdependent roles of mitochondrial phospholipid biosynthesis and protein import and assembly

The mitochondrial inner membrane has a unique composition of proteins and phospholipids, whose interdependence is crucial for mitochondrial function.

It is highly enriched in proteins specific to this membrane, the majority of which are encoded by the nuclear genome and imported from the cytosol. The lipid component contains the major classes of phospholipids found in all cell membranes, including phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine
(PS), and phosphatidic acid (PA), as well as phosphatidylglycerol (PG) and cardiolipin (CL), which are located predominantly if not exclusively in the mitochondria.   PE, PG, and CL are synthesized “ in house, ” whereas the others must be imported.

The endosymbiotic theory helds that  mitochondria appear to originate only from other mitochondria. 2 They contain their own DNA, which is circular as is true with bacteria, along with their own transcriptional and translational machinery. Mitochondrial ribosomes and transfer RNA molecules are similar to those of bacteria, as are components of their membrane.These and related observations led Dr. Lynn Margulis, in the 1970s, to propose an extracellular origin for mitochondria.

If the highly enriched  proteins specific to this membrane, the majority  are encoded by the nuclear genome and imported from the cytosol, then the endosymbiotic theory is nonsense, what i suspected for long.



1) http://jcb.rupress.org/content/184/4/469.full.pdf
2) http://www.ruf.rice.edu/~bioslabs/studies/mitochondria/mitorigin.html

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6 Re: The Mitochondrion on Tue Aug 11, 2015 9:56 pm

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http://cshperspectives.cshlp.org/content/4/9/a011403/T1.expansion.html

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7 Re: The Mitochondrion on Wed Aug 12, 2015 5:15 pm

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Mighty Mitochondria Conduct Energy Exquisitely 1

None of us could live without mitochondria.  These are the power centers ubiquitous in eukaryotic cells.  They contain molecular machines in factories whose jobs are to generate and conduct electrical currents.  The currents run turbines that packetize the energy in molecules of ATP, which are then used by most processes in the cell.  New discoveries continue to fascinate scientists with how mitochondria work.  Some scientists use their energy to find ways Darwinian evolution could build the machinery of life.
Background.  The energy source for animals is food; for plants, the sun.  Since animals eat plants, or eat other animals that ate plants, sunlight is the ultimate energy source.  In the chloroplasts of plants, sunlight energy is captured to produce energy-rich molecules, including glucose.  Mitochondria have inner and outer membranes.  The inner membranes are folded into protrusions called cristae that increase their surface area.  With the help of transporter machines, the mitochondrion takes in molecules (glucose, pyruvate, and NADH) from the cytosol into its outer and inner membranes into the interior where, with the aid of oxygen and a large number of enzymes and cofactors, electrons are transferred to oxygen through five complexes of machines.  The first three, called NADH dehydrogenase (Complex I), cytochrome c reductase, and cytochrome c oxidase, provide an “electron transport chain” that is used to pump protons into the space between the mitochondrion’s inner and outer membranes.  The protons return through the inner membrane via the fifth machine, the turbine-like rotary motor ATP synthase (see CMI), which uses the proton motive force generated by the other machines to synthase ATP.  Although cells can generate ATP without oxygen (anaerobic respiration), producing it through the mitochondrial machinery is much more efficient.  On a busy day you produce approximately your body’s weight in ATP.  This entry will look at some of the recent discoveries about the machinery of mitochondria.

Machine spacing:  An abstract on PNAS (8/29/2011, 10.1073/pnas.1107819108) described what new images of mitochondria using single particle cryoelectron tomography revealed.  Dudkina et al. could see how Complexes I, III, and IV are organized in mitochondria from cow hearts.  The spacing affects how the complexes interact.  “Surprisingly,” the Dutch and Swiss scientists said, “the distance between cytochrome c binding sites of complexes III2 and IV is about 10 nm.”  Ten nanometers is quite a bit at this scale.  Fortunately, there is a molecular glue – fat – that keeps them in place: “Modeling indicates a loose interaction between the three complexes and provides evidence that lipids are gluing them at the interfaces.”

Architectural machines:  PhysOrg reported on research at the University of Freiburg in Germany that identified another large machine whose job is to keep the inner and outer membranes from detaching.  “The researchers identified a huge molecular machine made up of six different membrane proteins required for attaching the cristae to the envelope of the mitochondria in the unicellular model organism baker’s yeast,” the article said.  “The data show that the defects in the protein complex trigger the detachment of the cristae, which in turn results in significant growth disturbances in the cell.”  Science Daily’s coverage called the structures produced by these machines the “supporting pillars of the structure of cellular power plants”.

Power plant placement:  Current Biology summarized a finding about how mitochondria are placed along the cell’s highway system.  “In fission yeast, microtubules control mitochondrial position by a mechanism that is dependent on microtubule dynamics but not motor proteins,” Liza A. Pon wrote in the Sept 13 issue of Current Biology (21:7, 10.1016/j.cub.2011.07.035). “A new study now reveals the molecular basis for this novel mechanism of organelle movement.”  In essence, mitochondria do not ride the rail cars (dynein and kinesin) like other organelles; they fasten to the tracks which shorten and stretch to put them where needed.  “This binding results in the uniform distribution of mitochondria as elongated tubular structures by two mechanisms: first, microtubule bundles serve as a scaffold to maintain the position of the organelle; and second, elongation of microtubules results in extension of mitochondria toward the cell tip.”  Another reason for the unusual mode of distribution may be to ensure that mitochondria (which divide by their own mechanism, with their own DNA) end up correctly in the daughter cells after cell division.

Mitochondrial division:  “New research from the University of California, Davis, and the University of Colorado at Boulder puts an unexpected twist on how mitochondria, the energy-generating structures within cells, divide,” an article on PhysOrg began.  The researchers found that “mitochondrial division overwhelmingly occurred at points where the two structures, mitochondria and ER [endoplasmic reticulum], touched.”  Why is that?  “Their study indicates that ER tubules first squeeze the mitochondrion, then dynamin-related proteins assemble on the surface to complete the job.”  They called this finding that “transforms our view of cell organization” a “paradigm shift in cell biology.”  Proper controls on mitochondrial division are vital.  “Defects in mitochondria have been linked to a wide range of degenerative conditions and diseases, including diabetes, cardiovascular disease and stroke.”

Mitochondrial genome:  Since mitochondria are approximately bacteria-sized, and contain their own DNA which they replicate with their own machinery, proponents of evolution believe that at some time in the history of life the first eukaryote engulfed a free-living bacterium and developed a symbiotic relationship with it.  Whether this theory of “endosymbiosis” is defensible is a question for another time, but PhysOrg did have some news about the machine that transcribes mitochondrial DNA, “mitochondrial RNA polymerase” (an analogue of the RNA polymerase in the nucleus).  Scientists at the Ludwig-Maximilians-Universitat Munchen were able to image the 3-D structure of this molecular machine in atomic detail.  They found similarities to the RNA polymerases found in phages (viruses that attack bacteria) and speculated those as the source of mitochondrial RNA polymerase.  But they also found that this machine is not a lone ranger: “In particular, the structure explains why two other protein factors are necessary to enable the RNA polymerase to bind at the right site on the DNA, and to transcribe the genetic information from this location,” one of the scientists said.  Interestingly, one of the machine complexes (Complex II) gets its genes from the cell nucleus.  The mitochondrial genome is passed on through the female.

Why you’re so tired:  Science Daily reported on work from McMaster University that may explain some couch potatoes.  They may be missing genes that generate mitochondria.  Mice with defects in the AMPK gene had fewer mitochondria and less energy.  Professor Gregory Steinberg explained, “When you exercise you get more mitochondria growing in your muscle. If you don’t exercise, the number of mitochondria goes down. By removing these genes we identified the key regulator of the mitochondria is the enzyme AMPK.”  It’s not an excuse, of course; you can increase your mitochondrial count through exercise.

How did this all evolve?  “The mechanism of oxidative phosphorylation is well understood, but evolution of the proteins involved is not,” wrote a team of three scientists from Alaska and Canada in a paper entitled, “Positive Darwinian Selection in the Piston That Powers Proton Pumps in Complex I of the Mitochondria of Pacific Salmon” (PLoS ONE 6[9]: e24127. doi:10.1371/journal.pone.0024127).

 So they decided to address the question.  Readers might remember the amazing discovery that Complex I uses a piston-rod mechanism to pump protons in the electron transport chain.  Now, Garvin, Bielawski and Gharrett looked for evidence of positive Darwinian selection for these pistons in salmon, but is their answer just a fish story?  In a sense, yes; they only looked for evolution within one kind of fish: “These data implicate Complex I, specifically the piston arm of ND5 where it connects the proton pumps, as important in the evolution of Pacific salmon.”  They did not attempt to explain where the pistons came from in the first place; they only discussed slight changes in the amino acid sequences in the proteins for part of Complex I between salmon species, which they attributed to “positive selection” (natural selection acting for a positive change in function, or innovation).
In passing, they pointed out some interesting facts about mitochondria.  Mitochondrial genes tend to accumulate mutations faster than nuclear genes.  “The rate difference was previously thought to be due to the lack a proof reading activity by the mitochondrial DNA polymerase… but recent work suggests the replication machinery does indeed proof read,” they said.  “A current theory posits that free radicals or reactive oxygen species, which are a byproduct of superoxide production by complexes of the oxidative phosphorylation system, damage the mitochondrial DNA (mtDNA) and produce a higher mutation rate.”

Bad mutations, they admitted, have disastrous consequences on human health, but then they assumed the converse: “It follows that other mutations may have beneficial effects on metabolism and thereby positively affect fitness.”  That’s a logical fallacy; other mutations might simply be neutral.  Just because some brickbats harm computers, it doesn’t follow that other brickbats will have beneficial effects.  They offered some weak empirical evidence to try to back that statement up – evidence they admitted is countered by other evidence.   So did they find evidence for positive Darwinian selection?  Is there a new function or improvement of function in salmon due to mutations in the mitochondrial DNA?  (Remember, they were only looking at the piston arm in Complex I of a five-machine system.)  Not really.  They used models, Bayesian analysis and phylogenetic methods to see if mutations differed from what would be expected if purely random or due to neutral drift, and if non-synonymous substitutions outnumbered synonymous substitutions (a synonymous substitution yields the same amino acid).  Then they tried to see if the mutations occurred in functionally important parts of the Complex I piston arm they were studying.  Of the seven candidate substitutions they found, only two were long-term, they said.  They also pointed out that their study was only the third of its kind (looking for positive selection in the mitochondrial genome).

In their Discussion section, they put their best foot forward.  “We observed that changes in the piston arm and, consequently, proton pumping, may have influenced fitness during the evolution of Pacific salmon species.”  But they didn’t tell the fish they were better off thanks to Darwin.  The mutations might do something: “it is likely that the positively selected mutations influence the electrochemical gradient, which is comprised of both a voltage potential and a difference in pH,” they suggested, but they were not ready to say that it actually helped the salmon get more energy, avoid reactive oxygen species, live longer, or anything else.  In fact, any connection between these seven mutations and a functional benefit to the fish had to be shuttled off to the future: “When a higher resolution structure becomes available, it should be possible to determine which of the specific amino acids in the ND5 piston arm interact with which proton pumps and the nature of the changes in the interactions that result at the sites under positive selection,” they concluded.  “This might provide information to determine if the piston arm is more tightly or loosely coupled to the pumps and therefore if pumping is made more or less efficient by the amino acid substitutions.”  So very little was actually learned by this evolutionary exercise.  In fact, they stated outright, “It is not possible to correlate the selected amino acid sites with Pacific salmon life-history at this point.”  To do that, someone would have to do field studies: “Empirical studies that established functional differences among species would make this connection possible.”  Maybe someone could take the salmon under controlled conditions and compare their oxidative output.  Even so, they are still all salmon, and they seem to get along quite well in their habitats. [Note: even creationists can accept diversification of salmon from an original created kind, so their findings, even if they did support positive selection, would not differentiate between creation and evolution.]

The kicker is in the last two paragraphs.  Despite their boast that “Our discovery of positive selection in a protein that is central to energy metabolism establishes an explicit connection between molecular evolution, protein function, and respiration,” they had just let the cat out of the bag in the prior paragraph: “Our SCA identified potentially important regions within the ND5 protein with respect to the sites under selection. However, this may have been simple phylogenetic signal, and we were not able to identify specific sites that were coupled to the positively selected sites with any certainty.”
Doggone; we just read that whole paper for nothing?  This is like government waste: lots of verbiage, lots of paper, with little to show for it.  They generated pages of models, Bayesian analysis, sequence comparisons, and at the end, out popped seven mutations that they couldn’t tie to any improvement for the salmon, other than that they didn’t get proof-read out.  Then they tell us that they couldn’t say anything for certain!

All the while, the wonders of mitochondria and of salmon were staring them in the face.  Pacific salmon turn their food into energy through a complex series of molecular machines inside an organelle containing genetic information that is transcribed, copied and proof-read by other molecular machines.  ATP synthase, the last machine in the respiratory chain, is a marvelous rotary engine that is irreducibly complex, pumping out ATP like gangbusters all the time (see CMI).  Then the fish take this ATP energy and “smell” their way up miles of river, leaping up waterfalls with all that chemical energy, to find the exact spot where their parents spawned them in prior years.  Those wonders scream “design!” – but choosing to ignore it, the Darwinists, focused on a few base pairs in one enzyme of the machine, look for tiny bits of wee changes that might vindicate Charlie against the mountain of evidence against him.  Pity is hardly a sufficient emotion for these ingrates.  We hope other scientists will use their brain ATP for nobler pursuits.

Energy balancing act: 2  Cells have to use oxygen without being burned by it.  In Nature 11/09,1 Toren Finkel described the delicate way mitochondria deal with their explosive fuel without polluting their environment.

Much like any factory producing widgets, mitochondria consume carbon-based fuels.  Their product is ATP, the energy currency of the cell.  Nonetheless, just like factory smokestacks, mitochondria also release potentially harmful by-products into their environment.  For mitochondria, these toxins come in the form of reactive oxygen species (ROS) that include superoxide and hydrogen peroxide.  In turn, these oxidants can interact with other radical species or with transition metals to produce by-products that are even more damaging.  To combat ROS production, the cell has evolved a number of sophisticated antioxidant defences, including enzymes such as superoxide dismutase to scavenge superoxide, as well as catalase and glutathione peroxidase to degrade hydrogen peroxide.

Finkel did not explain how these sophisticated mechanisms might have evolved, except to assert that mitochondria are “tiny and evolutionarily ancient energy-producing organelles.”  He did consider a claim that they contain a “design flaw” because they leak measurable amounts of reactive oxygen species.  Is this a bug or a feature?

If ROS synthesis is so bad, and a molecular solution so apparently straightforward, why has this 'design flaw' not been eradicated during the billions of years of evolution?  There are many possible answers, but one is that the notion that ROS from the mitochondria are solely harmful could be incorrect.  Indeed, substantial evidence exists that ROS generated in the cytoplasm could have vital signalling functions, and this might also be true for oxidants derived from mitochondria.

On closer inspection, then, it appears that “a homeostatic loop exists between mitochondria and ROS and that this loop is, at least in part, orchestrated by PGC-1alpha.”  This, in turn, stimulates the production of more oxidant-sweeping molecular machines.


1) http://crev.info/2011/10/111007-mighty_mitochondria/#sthash.VklKO7HK.dpuf
2) http://creationsafaris.com/crev200611.htm



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8 Mitochondria and Endothelial Function on Fri Aug 14, 2015 8:29 am

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Mitochondria and Endothelial Function 1



Conceptual illustration of the mitochondrial life cycle and the contribution of mitochondrial dynamics and mitophagy to quality control. Biogenesis is regulated by peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α), which activates nuclear respiratory factor (NRF)-1 and NRF-2 and transcription factor A mitochondrial (TFAM) and transcription factor B mitochondrial (TFBM). Mitochondria undergo cycles of fusion to form elongated mitochondrial networks and fission into smaller individual organelles. Fusion is mediated by mitofusin (MFN) 1, MFN2, and optic atrophy protein 1 (OPA1). Fission is mediated by dynamin-related protein-1 (DRP1) and fission 1 (FIS1). During their normal lifespan and in the setting of increased oxidative stress, damage to mitochondrial components accumulates. Fission provides a mechanism to isolate damaged components for elimination. Mitophagy involves mitochondrial depolarization, retention phosphatase and tensin homolog–induced putative kinase protein 1 (PINK1) in the mitochondrial membrane, and recruitment of Parkin, which targets the mitochondria to autophagosome. P62 also plays a role in targeting cargo to the autophagosome and is subsequently degraded during active autophagy. Assembly of the phagosome involves beclin-1 and conjugation of microtubule-associated protein 1 light chain 3 (LC3) onto phosphatidylethanolamine to form of LC3-II. (Illustration Credit: Ben Smith).18



1) http://circres.ahajournals.org/content/112/8/1171.figures-only

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9 Mitochondria: Spaceships of Life on Sun Jan 10, 2016 7:20 am

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 Mitochondria: Spaceships of Life

http://reasonandscience.heavenforum.org/t2131-the-mitochondrion#4578

from Marcos Eberlin's excellent book : Life and the Universe by Intelligent Design

https://www.widbook.com/ebook/life-and-the-universe-by-intelligent-design?ic=1&returnUrl=%2febook%2fchapters%2flife-and-the-universe-by-intelligent-design




Figure 1. The mitochondrion: true cellular " space ship" of high technology that has its own DNA. Chance or design?

In 1898, the German microbiologist Carl Benda was amazed1 with an extremely intriguing organelle. Using advances in microscopes of the time, he noted that structures "floating" inside the cell and called them "mitochrondria". Benda believed that mitochondria would function as the "pillars of support" of the cells, thereby using the Greek words "myths" and "chondros" ("cartilage wires") to give them their name.  Benda's findings not arouse much enthusiasm, but gradually it was realized that mitochondria were true "cell spacecrafts" the highest level of sophistication and chemical technology. Soon it was discovered that mitochondria were essential  for life since they provided the energy for the cell. But the biggest revolution on the role of mitochondria occurred in 1963, when it was realized that they had their own genetic material. - called mitochondrial DNA (mDNA) And we humans have inherited this mitochondrial DNA only from our mothers, and when we sequenced it, we  discovered that we are all descended from a single woman - the "mitochondrial Eve," who already estimated to have lived only a few thousand years back.7  It is known today that mitochondria, cytoplasmic organelles, are present in almost all eukaryotic cells, do autopropagate, and are semi-autonomous energy suppliers for the cell through the production of adenosine triphosphate - ATP. Mitochondria, it was discovered also are extremely abundant, for example in neurons, and particularly important in chemical synapses, allowing neuronal communication, and are essential for maintaining the integrity and function of the neurons. I think, therefore I possess mitochondria. In the mitochondrial matrix, there are a lot of ribosomes, synthesizers of proteins.



Figure 2. Mitochondria provide energy, in a true "battery bank" for the flagellar motor of espermatozoides. Essential to Life, since we cannot live  without them. A nanomolecular architectural engineering was also used in the "spaceship" the mitochondria, to divide it into four compartments (Figure 1): A matrix is a real "soup of enzymes" containing high concentrations of several enzymes, and several identical copies of genomic mDNA mitochondrial, special mitochondrial ribosomes, tRNAs that direct protein synthesis in ribosomes carrying into the ribosome  each of the amino acids of Life, and several enzymes necessary for mitochondrial genes to be expressed. A Internal membrana, in turn, is folded into a lot of "crests" in a strategy to increase many times the total area of ​​its surface. This inner membrane performs various functions and contains several proteins, and in it are ingeniously "established" those wonderful nano cellular energy production plants - enzyme complexes known as ATP synthase . Various carrier proteins present in the inner membrane of mitochondria still regulate the entry and exit of metabolites in the array. Furthermore, the proton gradient that drives the ATP synthase, which is the source of chemical energy, is established across the inner membrane, as its structural conformation finely tuned for this purpose, is impervious to metal ions and most of "molecules loaded ". The outer membrane, which, unlike the inner membrane is a permeable mass of molecules up to 5 thousand Da, has a large  protein which forms channels called porins,and the presence of other proteins which are involved in the synthesis of internal lipids, which are converted into substrates which can be metabolized in the array.But a compartment beyond of spectacular of mitochondria is the intermembrane space, which also contains many enzymes that leverage the ATP generated in the matrix to phosphorylate some nucleotides. This space is also the reservoir and allows protons which drives ATP synthesis. And the wonders of the mitochondrion seems inexhaustible. For it has been found that they are dynamic organelles,  able to move bidirectionally. And that this movement takes place along  Nanomolecular roads present in cells via microtubules and with the help of protein engines - for example the kinesins (Chapter 65), and adapter proteins (Figure 4). Thus, mitochondria move "a  Sugar Loaf cable car", hanging on protein strands, and driven by molecular nanorobots, the kinesins. A  "symbiotic" association  of real extreme complexity, beyond irreducible complexity, and genius, mixed with pure information, occurs inside a molecular nanorobot within a high tech " space-ship", which itself carries a nano power plant, full of ATP synthases. Look at the vast amount of processes that occur there, and we have much yet to discover about them. A multitude of chemical reactions, synchronized processes, Krebs cycle, channel Na + and K +, and so on.



Figure 3. The dynamic movement of mitochondria along microtubules assisted by nanomolecule motors - the kinesins. A synergy of highways, engines and nanomolecular spaceships. Without this high-tech "cell spaceship" which is the mitochondria, life we ​​see today, and in its most diverse forms of extreme complexity and sophistication, would then become unfeasible. Mitochondria thus forms one of the many spectacles of nanotechnology , irreducibly complex, ingenious foresight, functional aperiodic information, to enable abundant life, mine and yours. But if we look at the theories that have been proposed for the "evolution" of the mitochondria, we see there the use of terms and for word like this: "believes", "emerging", "learn" and "believe" Faith and beliefs, things contrary to scientific "common sense". In that "endosymbiosis" proposed by Lynn Margulis in 1981.? , the first one being swallowing another and tolerating it over time, inside. And "obvious" evidence is obtained from mere similarities. A true "chemical and genetic miracle", the "creation" of mitochondria and his "green cousin", the chloroplast, are presented as a consequence of such a "symbiotic association" between stable organizations during the evolutionary process. But see how many beneficial mutations that would require, and what time they need to settle, and remember that mitochondria appears to be nearly as ancient as life on this planet, if not equal. Just because they are similar to bacteria, mitochondria evolved from them? "Appearance" is "clear evidence" of something? They do the same with humans and chimpanzees.






Figure 4. endosymbiosis models proposed for the "evolution" of mitochôndrias.

----------------------------

1. The "discovery" of mitochondria is controversial, and there are reports of its previous observation, but Kendall Haven in the book "100 Greatest Science Discoveries of All Time" (Libraries Unlimited, 2007) cites Carl Benda as the discoverer of mitochondria, see the Appendix 2.

_______
1. Mitochondria: Form and Function, Cell, Volume 147, Issue 4, p. 711, 713, 11 November 2011. http://www.cell.com/abstract/S0092-8674(11)01280-3
2. See a text , more than  interesting and "didactic" found in Wikipedia on the Origin of Mitochondria: There are two hypotheses about the origin of mitochondria: endosymbiotic and autogenous. The endosymbiotic hypothesis suggests that mitochondria were originally prokaryotic cells, capable of implementing oxidative mechanisms that were not possible for eukaryotic cells; they became endosymbionts living inside the eukaryote.[79] In the autogenous hypothesis, mitochondria were born by splitting off a portion of DNA from the nucleus of the eukaryotic cell at the time of divergence with the prokaryotes; this DNA portion would have been enclosed by membranes, which could not be crossed by proteins. Since mitochondria have many features in common with bacteria, the most accredited theory at present is endosymbiosis.[79][80] A mitochondrion contains DNA, which is organized as several copies of a single, circular chromosome. This mitochondrial chromosome contains genes for redox proteins, such as those of the respiratory chain. The CoRR hypothesis proposes that this co-location is required for redox regulation. The mitochondrial genome codes for some RNAs of ribosomes, and the 22 tRNAs necessary for the translation of messenger RNAs into protein. The circular structure is also found in prokaryotes. The proto-mitochondrion was probably closely related to the Rickettsia.[81] However, the exact relationship of the ancestor of mitochondria to the alphaproteobacteria and whether the mitochondrion was formed at the same time or after the nucleus, remains controversial.[82] 
A recent study[83] by researchers of the University of Hawaii at Manoa and the Oregon State University indicates that the SAR11 clade of bacteria shares a relatively recent common ancestor with the mitochondria existing in most eukaryotic cells. The ribosomes coded for by the mitochondrial DNA are similar to those from bacteria in size and structure.[85] They closely resemble the bacterial 70S ribosome and not the 80S cytoplasmic ribosomes, which are coded for by nuclear DNA.
The endosymbiotic relationship of mitochondria with their host cells was popularized by Lynn Margulis.[86] The endosymbiotic hypothesis suggests that mitochondria descended from bacteria that somehow survived endocytosis by another cell, and became incorporated into the cytoplasm. The ability of these bacteria to conduct respiration in host cells that had relied on glycolysis and fermentation would have provided a considerable evolutionary advantage. This symbiotic relationship probably developed 1.7[87] to 2[88]billion years ago.
A few groups of unicellular eukaryotes lack mitochondria: the microsporidians, metamonads, and archamoebae.[89] These groups appear as the most primitive eukaryotes on phylogenetic trees constructed using rRNA information, which once suggested that they appeared before the origin of mitochondria. However, this is now known to be an artifact of long-branch attraction—they are derived groups and retain genes or organelles derived from mitochondria (e.g., mitosomes and hydrogenosomes).[1]
7. "Calibrating the Mitochondrial Clock" Ann Gibbons Science, 279, 28, 1998.

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