Mitochondrial Proliferation and mtDNA Content in Folate Depletion and Other Contexts

This is a great article showing that folate depletion produces significant damage to mtDNA in the liver, reduces mtDNA content, and induces mitochondrial proliferation and increases in mitochondrial gene transcription. I think the changes in mtDNA could be explained by an increase in uracil misincorporation into mtDNA, in response to intramitochondrial folate depletion, as the authors found, and interruption of the folate cycle enzymes. The authors didn't mention the role of an increase in the dUTP/dTTP ratio as a cause of the large deletions and oxidative stress, but I think that's an important underlying mechanism. Uracil misincorporation can lead to double-strand breaks and large deletions. The DNA damage from folate depletion sounds mild, but it's the secondary mechanisms of damage, not the uracil misincorporation per se, that produce these kinds of major changes in mitochondrial functioning. The mitochondrial proliferation is actually what one would expect, and mitochondrial proliferation tends to be a sign of (or at least to accompany) respiratory chain dysfunction:

http://jn.nutrition.org/cgi/content/full/137/9/2036#BIB29
(pubmed: http://www.ncbi.nlm.nih.gov/pubmed/17709439?dopt=Abstract) (Yi-Fang Chu et al., 2007)

One early mechanism is the activation of AMP-activated protein kinase (AMPK) by a decrease in the ATP/AMP ratio (AMPK is very sensitive to changes in the AMP content, and decreases in the ATP levels imply that the AMP levels are being increased concomitantly).

This article shows that mitochondrial proliferation in cardiac myocytes was associated with increases in mtDNA content and in the production of reactive oxygen species. The mitochondrial proliferation occurred, at least in part, through the PPAR-alpha/PGC1alpha pathway:

http://content.onlinejacc.org/cgi/content/full/50/14/1362
(pubmed: http://www.ncbi.nlm.nih.gov/pubmed/17903636) (Mariangela Sebastiani et al., 2007)

It's interesting that either an increase or decrease in the mtDNA content can be associated with pathology. I think one just has to look at the cellular and physiological context. It seems pretty clear that ATP depletion and evidence of oxidative stress and poor oxidative metabolism (increased lactate/pyruvate ratio, lipid accumulation in the liver, etc.) are more telling factors than a change in the mtDNA content per se. But a lot of the time, mitochondrial proliferation is not a good sign. The increased numbers of mitochondria just don't compensate for the ATP depletion and tend to make the situation worse by worsening oxidative stress, etc.