Reactive oxygen species production in the mitochondrial matrix: implications for the mechanism of mitochondrial mutation accumulation

Interestingness: 3

By Aubrey D.N.J. De Grey. Rejuvenation Research. Spring 2005, 8(1): 13-17. doi:10.1089/rej.2005.8.13.

Comparison between three different theories of mitochondrial DNA mutation, and the how to interpret new findings that alpha-ketoglutarate dehydrogenase (AKDH), an enzyme in the mitochondrial matrix, makes hydrogen peroxide and possibly superoxide when exposed to high concentrations of NADH.

One of the theories is the vicious cycle hypothesis, in which mutations in the mtDNA trigger creation of superoxides which then trigger more mtDNA mutations, etc. Another is de Grey's own survival of the slowest (SOS) hypothesis described earlier in the blog. The third is the crippled mitochondrion (CM) (underspecified) hypothesis in which mutant mitochondria are stimulated to replicate by some mechanism internal to the mitochondria.

de Grey claims that the vicious cycle theory is refuted by the commonality of mutations that would get rid of the possibility to make superoxide (mtDNA deletions that get rid of the genes encoding for Complex I and III, and also get rid of at least one tRNA, for which there are no redundancies in the mtDNA), and also by the observation that the mutations in all the mitochondria's DNA tend to be the same within any one individual cell.

Differences in predictions by the other two theories:

SOS	CM
Autophagy of mitochondria selects mitochondria with damaged membranes	No prediction
Loss of ATP-synthase does not preferentially replicate	All functional losses replicate
No prediction	Cell overpopulated with mitochondria comes before or at the same time as loss of respiratory function
ROS production by mutant mitochondria eliminated	No prediction

That last prediction by the SOS hypothesis, lack of ROS production, seems to run counter with findings that oxidation-damaged DNA and RNA are found in respiration-deficient muscle fiber segments. This is the reason for bringing up the new findings of generation of ROS by AKDH when under high concentration of NADH, a state de Grey claims would be more common in mitochondria with broken respiratory chains, giving the oxidised DNA an alternate cause.