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Lecture 18

BIOC13H3 Lecture 18: BIOC13 Lecture 18

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Biological Sciences
Jason Brown

BIOC13 Lecture 18  There are 2 shuttles that can bring nadh into the matrix  G3P shuttle system is the first shuttle  In the cytosol you find an enzyme called G3P dehydrogenase, it oxidizes NADH and pass e on to dihydroxyacetone phosphate, which is an intermediate of glycolysis, forms g3p  There’s an enzyme on the outside face of the mitochondrial membrane, a mitochondrial version of the same enzyme, carries out same reaction  Major difference is that mitochondrial version will use FAD as its electron acceptor, rather than NAD, making FADH  Then enzyme will pass electrons from FADH to ubiquinone in the membrane and from there the electrons are passed to the rest of the electron chain  The electrons from NADH have entered the ETC but the physical NADH has not  NADH, FADH and Q have different reduction potentials  FAD has a higher more positive reduction potential than NADH  By moving electrons from NADH to FADH we are moving electrons from a low red poten compound to a high one and so there will be a release of free energy  There is no mechanism to conserve the free energy released  In reality this shuttle system is an inefficient shuttle system because does not conserve  Second shuttle system is the malate aspartate shuttle system  In the cytosol there is an enzyme called malate dehydrogenase  Its job is to take oxaloacetate and nadh and pass electrons from NADH to oxaloacetate, thereby oxidizing NADH and reducing oxaloacetate to malate  There is a transporter in the imm that will allow malate to enter, once the malate enters the mitochondrial matrix, that’s where the malate dehydrogenase takes it and oxidizes it back to oxaloacetate, and the electrons taken are put on NAD+ to make NADH  This is a more efficient system because moving electrons from an NADH to an NADH  So there is not much free energy released, less of a loss of free energy  Its not as efficient as you might think because in order to move electrons, the laws of TD tell us there must be some difference in reduction potential for the reaction to proceed  It will only happen if the ratio of NADH to NAD in cytosol is higher than the ratio in the matrix  The ratio between reduced and oxidized form determines its intracellular reduction potential, so if we have high concentration of NADH relative to NAD+ in cytosol the reduction potential of that nadh will be lower and the situation is opposite in the matrix where we have lower concentration of NADH and relatively high concentration of NAD+ making the reduction potential a little more positive, giving favourable passing of e from low reduction to high reduction potential  Its rare for the ratio of nadh to nad to be high in cytosol and low in mitochondria because generally its reverse and not favourable to move from cytosol nadh to matrix nadh  So how does it happen, how does the shuttle system work?  We couple it to some exergonic process  When malate is being brought across the membrane, there are protons flowing along  As we turn oxaloacetate into malate in the malate dehydrogenase reaction, there is a proton that is incorporated into the structure of the malate, as it goes across imm and becomes oxaloacetate then that proton is dropped off  Essentially, we are carrying protons across the mitochondrial membrane  Using that gradient to power the shuttle system  Some of that gradient to power that transport, this is still the more efficient shuttle  Might think that once oxaloacetate is formed it is sent out so that we can keep running the pathway, but imm is not permeable to oxaloacetate, so there’s no transporter to get the oxaloacetate across, but we need it back across to keep running shuttle system  Second part of the system comes into play  The oxaloacetate gets trans animated, meaning that an amino group from glutamate is taken off glutamate and passed onto oxaloacetate, and now it becomes aspartate and glutamate having lost amino group becomes a ketoglutarate  The aspartate is shuttle out of the mitochondria and once it is out there we do the reverse, take amino off aspartate and put it on the a ketoglutarate to get back the oxaloacetate  As aspartate is shuttled out, a proton is coming in, this serves to dissipate the proton gradient  Serves to drive the shuttle system even though it is not favourable to move the e  Can exploit the difference when it comes to which shuttle system will dominate  We have a choice to use the efficient one or less efficient one  Study took human participants and put them through 8 weeks of training and they measured the level of enzymes of the 2 shuttle systems both before and after the training  Enzymes like malate dehydrogenases or transaminase or G3P dehydrogenase  Looking for what’s the general trend in the activities of the enzymes  What you notice is that the malate aspartate enzyme increase their activity following endurance training and the G3P enzymes decrease their activity after the training  Since malate pathway is efficient, this makes sense because as an athlete you want to have an efficient metabolism to conserve as much of the free energy to power muscle activity for long periods of time  Endurance training causes us to develop a more efficient metabolism so less energy is lost as heat  Opposite is the case in this second study  Took rats and exposed them to the cold, and rats wants to maintain high body temp  Rats want their metabolism to be inefficient so that they are converting free energy into heat and using that to keep warm  Rats exposed to -20 for 20 min, you see that their body temperature goes down  They measured the enzymes and wanted to know the rates of respiration  The aKG rates are still mostly the same  The malate shuttle activity stays mostly the same in the cold, but the G3P activity does significantly increase in the cold  This means that we are running a more inefficient metabolism and that means an increase in heat production which is helping keep the rat from getting too cold  The pieces in the ETC are in all organism, but mammals have the simplest version and most studied, other organisms add complexity to their ETC  It comprised of 4 protein complexes, 2 mobile carriers (ubiquinone and cytochrome c)  Complex 2 is the same as succinate dehydrogenase in krebs cycle (same protein)  Most often when people draw diagrams of ETC they always include ATP synthase with it  But ATP synthase is not part of the electron transport chain so we should stop referring to the atp synthase as complex 5  The electrons don’t flow in the order from 1-4  Electrons come in to 1, then to Q then to 3, then to 4, no electrons to 2  Electrons can come in to complex 2, then to Q then to 3, then to 4  Complex 1 and 2 represent different entry points  Never any exchange between C1 and C2  When you look at textbook drawings they always show one member of each complex  But for every complex 1, there is 1 complex 2, 3 complex 3 and 6 complex 4  Complex 1 is representing about 42 proteins that come together to form the complex  If you were to study these protein complexes you can employ 2D gel electrophoresis, allows you to take proteins that make up the electron transport chain and separate them  Blue native: any proteins that interact together in cell, will keep those interactions in tact, this allows you to see which kinds of proteins interreact in the cell  You end up getting 4 bands, one for each complex, so all of the proteins in the complex 1 are seen together as 1 band  In the second dimension you want to separate the individual proteins in a complex  You can run an SDS page and this will disrupt the interaction between protein and show you the individual proteins under the single band  The complex 1-3 means that in our cells the individual proteins come and bind together  50 years ago the way people thought of the ETC as existing separately from all the other complex, not touching each other, far apart  Many biochemical reactions are where you create a product, which the dissolves to find the next thing to bind  For some you see C1+3 and in the last 10-15 years we see that complexes start to come and bind together  Before people thought of ETC complex as existing separately as individual complexes  Respiratory supercomplexes, where c bind together and allows for substrate channelling  This will make metabolism more efficient because now when electrons are passed to Q then it can easily pass electrons to complex 3  It will minimize electrons escaping prematurely, making metabolism more efficient  Now we see that they may both be correct and mitochondria might switch between each other, when in super complex form they are more efficient (plasticity model)  Work has been done to find to regulate proteins that regulate the transition  This is done by OPA1 (mitochondrial shaping protein) its able to determine the shape of the fold of the imm (cristae)  Imm is highly folded, its opa1 job to determine just how tight the folding is  Pulls the inner membrane regions together, when that happens it causes the complexes to come together and makes it more efficient  When you delete opa1 there is nothing to keep the cristae together, and promotes inefficiency in metabolism because the complexes are not close together  Oma1 job is to proteolytically cleave and thereby deactivate opa1  Mice on left is oma1 knock out, doesn’t express oma1, on right we have a wild type mouse with oma1  Mice is fatter when you lose opa1, because you have cristae that unfold, respiratory supercomplexes come apart and that promotes inefficiency in metabolism  If you have efficient metabolism you can better conserve free energy and if oyu can conserve a lot of free energy it promotes obesity  In oma1 knock out, there is no oma1 to
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