May 25, 2005
Mitochondria Aging Leads To Atherosclerosis And Heart Disease

The mitochondria are a subcellular organelle (a sort of cell within a cell) that break down sugar to generate energy molecules used throughout the cell. Clay F. Semenkovich, MD at the Washington University School of Medicine and colleagues report that failures in mitochondria due to aging are suspected of causing atherosclerosis and heart disease.

The research team genetically engineered mice to have especially leaky mitochondria in their blood vessel cells. It found that although normal mice very rarely acquire atherosclerosis, the mutant mice all developed the disease, even when fed on a low-fat, low-cholesterol diet. The results of the experiment appear this week in Nature.


They speculate that an increased flow of reactive oxygen damages the blood vessel's walls. The body then mounts an immune response to repair this damage, and scientists have already established that cells trying to fix arterial damage can create problems. These immune cells attract a form of cholesterol that sticks to arterial walls, forming plaques.

Mentally I file this under "Totally Unsurprising". Mitochondria have their own DNA for some of their proteins. Some gerontologists (e.g. Aubrey de Grey) theorize that the mitochondrial DNA (mtDNA) acts as a sort of Achilles Heel in cellular metabolism and cellular aging. Very reactive chemical compounds get generated in mitochondria by breaking down sugar and some of those compounds occasionally break loose and fly into the mtDNA causing damage. So mtDNA might accumulate damage at a much faster rate than DNA in the nucleus.

The increased rate of mutational damage to mitochondrial DNA eventually disables some of the genes that a mitochondrion needs to generate energy. Given that many other mitochondria in a cell could step in to make up the shortage of energy from a single damaged mitochondrion one might not expect damage to one or two mitochondria to make much difference. But note how the article talks about reactive oxygen generated by old mitochondria. The same mutations that cause mitochondria to stop breaking down sugar properly also are suspected of causing mitochondria to generate lots of free radicals. Those free radicals cause inflammation that, through some additional steps, cause hardening and clogging of arteries.

So what to do about this? As one of his Strategies for Engineered Negligible Senescence Aubrey de Grey proposes development of gene therapies to move mtDNA genes into the nucleus where they won't get damaged by mitochondrial metabolism.

This gives us a wonderful opportunity: rather than fixing mitochondrial mutations, we can obviate them. We can make copies of those 13 genes, modified in fairly obvious ways so that the TIM/TOM machinery will work on them, and put these copies into the chromosomes in the nucleus. Then, if and when the mitochondrial DNA gets mutated so that one or more of the 13 proteins are no longer being synthesised inside the mitochondria, it won't matter -- the mitochondria will be getting the same proteins from outside. Since genes in our chromosomes are very, very much better protected from mutations than the mitochondrial DNA is, we can rely on the chromosomal copies carrying on working in very nearly all our cells for much longer than a currently normal lifetime.

This project needs a lot of work, though, even though it sounds simple. The 13 proteins of interest are actually quite difficult for the TIM/TOM machinery to process even when we "tell" it to do so, so we still need to work on making that part easier. But there has been good progress in this area in the past couple of years.

This latest report does not prove that mitochondrial aging is a major cause of plaque build-up in arteries. However, it is certainly consistent with this theory.

The development of gene therapy to fix the problem with mtDNA mutation accumulation still lies many years in the future. Semenkovich is looking for ways to change the amounts of omega 3 and omega 6 fatty acids available in cell walls in hopes that the inflammation response can be reduced so that perhaps the development atherosclerosis will be slowed.

"It would be interesting to figure out how to take essential fatty acids, get them into the vessel wall and see if you could treat atherosclerosis that way," said Semenkovich.

More omega 3 fatty acids from fish might help and I hope Semenkovich succeeds in his investigations. But I'd much rather have gene therapies that would rejuvenate artery and vein wall cells or cell therapies that would replace existing cells with younger and healthier cells.

Share |      Randall Parker, 2005 May 25 10:37 PM  Aging Studies

Fly said at May 26, 2005 12:16 PM:

Mitochondria are dynamic. They fuse together and split apart. I wonder how many of the mitochondria components are static and how many are rebuilt. Damaged mtDNA might be repaired or replaced during fusion with another mitochondria. (Has anyone explored this possibility?) Damaged mitochondria may be digested.

Mitochondria are dispersed throughout the cell and seem to be concentrated where ATP is needed most. My guess is that mitochondrial growth depends on signals in the local cell environment. Locating some mitochondrial genes in the mitochondria might be necessary for the mitochondria to respond to the local environment. There might also be scaling issues, as nuclear DNA might not produce sufficient proteins for the thousands of mitochondria needed in muscle and neural cells. (Or transporting certain proteins from the RER to the remote mitochondria could be inefficient. Nerve cells can be very long.)

Nuclear mitochondria genes are better protected than mtDNA. Also having mitochondrial genes in the nucleus helps prevent “selfish” mitochondria from evolving. (The cell is harmed but the “selfish” mitochondria produce more “offspring”.) So there are advantages to having most of the mitochondrial genes residing in the nucleus.

Mitochondria may represent a balance between the advantages of centralized nuclear DNA and the advantages of distributed mtDNA.

Randall Parker said at May 26, 2005 2:52 PM:


Aubrey de Grey's theory of several years ago (I don't know if he still sees it as viable) is that once a mitochondrion gets mutated to knck out a good chunk of its OXPHOS machinery it will divide more rapidly and within the cell that contains it that mitochondrion will out-compete non-mutated mitochondria.

No, damaged mtDNA isn't going to get fixed by mitochondrial fusion.

Fly said at May 26, 2005 9:51 PM:

Randall: “it will divide more rapidly and within the cell that contains it that mitochondrion will out-compete non-mutated mitochondria”

I remember de Grey suggesting that possibility. When experiments later showed that only a small percentage of aged mitochondria showed damage I believe de Grey looked for ways in which a few defective mitochondria could cause significant problems. I believe experiments have shown that there is little decrease in energy production as cells age. (Though I do remember a paper stating that aged muscle cells showed diminished energy production.)

The “out competing” seems to imply a model in which mitochondria resemble invading bacteria. I believe more recent results indicate that mitochondria are dynamic, merging and dividing frequently. (Unlike bacteria.) That should imply sharing mtDNA (which somewhat resembles a bacterial plasmid). If a gene is disabled by a mutation, then mtDNA from another mitochondria might provide a good gene copy, or provide sufficient mRNA, or provide enough of the missing protein, all ways that mtDNA damage might be limited by mitochondrial fusions.

“Therefore, mitochondrial fusion is essential for embryonic development, and by enabling cooperation between mitochondria, has protective effects on the mitochondrial population.”

If mtDNA damage is common I wonder how the quality of the mtDNA is conserved from generation to generation. The egg cell contains over a thousand mitochondria. How are defective mitochondria filtered? Perhaps random distribution of the mitochondria during each cell division results an uneven distribution of good and bad mitochondria. Cells with more good mitochondria might divide more rapidly.

(Many diseases are caused by mtDNA mutations. I wonder what percentage of the mitochondria is defective in these diseases.)

Here’s a link to an image of a yeast cell with a network of mitochondria dynamically changing:

Wendelina Saunders said at June 16, 2005 8:11 PM:

After reading this report, it sounds like this is a decease mostly by elderly people;
But I have a nephew who is less than two years old who has the decease, We are looking for anyone who can give us some information as to a possible cure for him.
Any information at all may help, Thank you


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