A proposed refinement of the mitochondrial free radical theory of aging

(((This isn't really part of the series. I was reading "A Mechanism Proposed to Explain the Rise in Oxidative Stress During Aging" in the series but it assumes that the reader is familiar with this paper. Since I found it interesting, I'm writing a summary of this one as well)))

Summary: Hypothesis is that cells get filled up with mutant mitochondria. This is because their membrane gets destroyed at a slower rate due to them being slower in producing free radicals. This leads to them not being destroyed by the cell recycling mechanism.

Interestingness factor: 7ish

Paper by Aubrey de Grey, published in BioEssays, 1997, volume 19, issue 2. (((can be gotten from http://www.sens.org/files/sens/AdGpubs.htm)))

(((Harder to summarise theoretical papers, since most of it tends to be important for the theory to hold)))

The paper makes the case that the replication of mutant mitochondria fills up cells with mostly useless mitochondria that do not feed the cell enough ATP, and that this is important for mammalian aging. I'll focus on the description of the mechanism of how mutant mitochondria supposedly get selectively replicated and come to represent most/all of the mitochondria in a cell, since that's the bit that's relevant to the paper in the Anti-Aging journal. I'll mostly ignore the importance of this to aging.

(((Reading up on mitochondria, and http://en.wikipedia.org/wiki/Electron_transport_chain#Electron_transport_chains_in_mitochondria helps)))

Mitochondria reproduce more frequently that the cells that contain them, especially if those cells don't replicate at all
(senescent). Their DNA (mtDNA) is not as well protected as nuclear DNA and is close to the reactive molecules that they produce. There are 13 genes in mtDNA that are not duplicated in the nuclear DNA and so are essential to the functioning of the mitochondria. They include proteins that form part of the respiration chain and the ATP generation. Therefore point mutations in those parts of their DNA would interfere with those functions. If there was a selective process which would preferentially replicate these mitochondria over the non-mutant ones, then mutants would dominate the cell and all/most mitochondria in the cell would have non-working or slow ATP production.

(((The most speculative part is the following))) Mitochondria damage their cell membrane in the production of the proton gradient. The process creates radical molecules that attack the lipids in their inner membrane. If the membrane is damaged enough small molecules from the interior of the mitochondrion will leak into the cytoplasm. The cell uses these as markers of damaged mitochondria and destroys it (by lysosomal degradation). Because the mutant mitochondria have faulty electron transport chains, their membrane degrades slower. This means they are left alive and reproduced when the cell thinks it needs more ATP (cell has to pick from the mitochondria that are alive). (((Tada!)))

Evidence offered for this theory: 1) Mitochondria in cells tend to share the same mutations, and these are different from the mutations in the cell next door. 2) Mutations that affect the ATP synthetising enzymes do not become popular among cells, because their transport chain is intact and therefore their membranes are just as damaged as non-mutant mitochondria (((this is offered as a prediction in the paper but he claims the result is provisionally known to be true)))

Refutations of potential counter-arguments. (((I'm restricting to only the ones that refer to the spread of the mitochondria again)))

1) Objection: Mitochondria have many copies of mtDNA, single mutation in one copy won't make much of an impact. Counter-counter: Some mutations will hang around and become homozyguous in all copies of a mitochondrion by genetic drift. Also, even arecessive mutation would have some small effect on electron transport and the mitochondrion only has to survive a little bit longer than the rest to be replicated.

2) Objections: Membranes get repaired. Counter-counter: Not all damage can be fixed.

3) Objection/question: Does a mitochondria with a damaged electron transport chain mechanism actually cause less damage on their inner membrane? Counter-counter: Yes. Three paths of lipid peroxidation: perhydroxy levels lower on the outside of an inner membrane of a slowly respiring mitochondrion, so will levels of ubisemiquinone. Metal-catalysed pathway still just as active probably (((I'm just parroting this bit. No idea if it's complete nonsense)))


Abstract follows:

Over recent years, evidence has been accumulating in favour of the free radical theory of aging, first proposed by Harman. Despite this, an understanding of the mechanism by which cells might succumb to the effects of free radicals has proved elusive. This paper proposes such a mechanism, based on a previously unexplored hypothesis for the proliferation of mutant mitochondrial DNA: that mitochondria with reduced respiratory function, due to a mutation or deletion affecting the respiratory chain, suffer less frequent lysosomal degradation, because they inflict free radical damage more slowly on their own membranes. Once such a mutation occurs in a mitochondrion of a non-dividing cell, therefore, mitochondria carrying it will rapidly populate that cell, thereby destroying the cell's respiratory capability. The accumulation of cells that have undergone this transition results in aging at the organismal level. The consistency of the hypothesis with known facts is discussed, and technically feasible tests are suggested, of both the proposed mechanism and its overall contribution to mammalian aging.