Interestingness: 4
Paper by Bernhard Kadenbach, Elisabeth Bender, Annette Reith, Andreas Becker, Shahla Hammerschmidt, Icksoo Lee, Susanne Arnold and Maik Hüttemann in the Journal of Anti-Aging Medicine, Volume 2, Issue 3, Fall 1999.
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This is more of a mitochondria biochem details piece, not directly related to aging. Most of it is too detailed for me to summarise or keep in memory or even follow.
Some interesting bits at the front that are not usually spelt out: out of the 13 proteins that mtDNA codes for, seven code for parts (out of 45) of NADH (nicotinamide adenine dinucleotide, protonated form) dehydrogenase (aka complex I), one for ubiquinol-cytochrome c oxidoreductase (aka complex III) (out of 11), three for cytochrome c oxidase (aka complex IV) (out of 13), and two for ATP synthase (out of some number I couldn't find). There's 5-10 mtDNA copies per mitochondrion, and 100-1000 mitochondria per cell.
It then describes two separate mechanisms of respiratory control. The first being due to the stimulation of ATP synthase by ADP triggering a lower proton motive force (deltaP) which trigger the proton pumps of the respiratory chain (NADH dehydrogenase, cytochrome c oxidoreductase and cytochrome c oxidase), kind of like an inverted system I think, with the final step pressuring the steps that come before it, but I imagine talking about the order here is completely wrong, they all happen at the same time. The second being due to the ATP/ADP ratio, with high ATP/ADP intramitochondrial ratio triggering a shut down of cytochrome c oxidase. This second method of control is bypassed by the presence of certain molecules, including 3,5-diiodo-L-thyronine, suggested as the mechanism of the short-term effects of thyoroid hormones, and palmitate (but not stearate, oleate or arachidonate).
The paper then does some studies showing that cAMP-dependent phosphorilation of complex IV enhances this ATP/ADP ratio control mechanism, and mitochondrial protein phosphatases reverse this enhancement. This second effect is shown mainly by adding a potassium fluoride which acts as a phosphatase inhibitor, and seeing the cAMP effect be stronger.
They also confirmed that it is mostly one mutant species of mtDNA that dominates a muscle fiber. They mapped a common deletion of mtDNA, probably that mtDNA4977 that was seen a couple of posts ago, and its occurrence varied between 0 and 0.06%, but corresponded with the bits of tissue that had malfunctioning complex IV.
They then speculate on how this phosphorilation/dephosphorilation mechanism is usually in balance, and is controlled by stressors and how when the ATP/ADP control mechanism is working, the proton gradient voltage is lower, and so less leakage of protons across the membrane occur, and less reactive oxide species are produced, and how this would be normally bypassed in a high caloric diet by the presence of palmitic acid, but the chain of reasoning is long and requires more concentration than I was willing to give it.
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Abstract follows:
The mitochondrial hypothesis on aging suggests stochastic stomatic mutations of mitochondrial DNA (mtDNA) as an important cause of respiratory-defective cells and the decline of energetic capabilities with increasing age. Reactive oxygen species (ROS), which are produced in the respiratory chain under stress conditions, are assumed to cause deletions and/or mutations of mtDNA. Using quantitative PCR, the stochastic distribution of the "common deletion" of mtDNA in human skeletal muscle tissue is shown. Recent data suggest that in vivo, under normal conditions, respiration is controlled by the intramitochondrial ATP/ADP ratio, via interaction of the nucleotides with subunit IV of cytochrome c oxidase, representing the rate-limiting step of the respiratory chain. Kinetic data are presented indicating that this "second mechanism of respiratory control" is turned on by cAMP-dependent phosphorylation of the enzyme and turned off by mitochondrial protein phosphatases. It is proposed that dephosphorylation of cytochrome c oxidase via "deleterious stress signals" results in increased mitochondrial membrane potentials and stimulated production of ROS in the mitochondrial respiratory chain. As a consequence, mutations of mtDNA would increase and aging would be accelerated. The inhibition of cytochrome c oxidase at high ATP/ADP ratios can also be abolished by low concentrations of free palmitate and high substrate pressure in the respiratory chain, supporting the notion that low caloric diet supports longevity.
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