Mitochondrial Aging Theory lacks definition

Disturbances in the function of mitochondrial DNA can accelerate the aging process in ways that are different than what was previously thought, according to a new Finnish study published in Nature Metabolism.

For almost half a century, mitochondrial DNA (mtDNA) mutations and oxidative stress have been asserted as major contributors to aging, as postulated in the mitochondrial theory of aging by Harman in the 70’s. The mtDNA Mutator mice were generated to test this hypothesis by two independent groups (Trifunovic et al. Nature 2004, Kujoth et al. Science 2005).

These mice accumulate mtDNA mutations are present with accelerated aging signs, including grey hair, thin skin, osteoporosis and anaemia, said a press release of University of Helsinki.

Therefore, a conclusion was made that mtDNA mutagenesis drives aging. However, despite rigorous studies by several groups, elevated oxidative stress has not been found in Mutator mouse tissues.

The current study published in Nature Metabolism proposes an alternative explanation for mitochondrial progeria: that mtDNA Mutator mice have compromised nuclear DNA maintenance in their stem cells.

The Mutator mice harbour a defective polymerase-gamma enzyme, and present with pronounced mtDNA mutagenesis. Mutator mouse is the only mitochondrial model which manifests accelerated aging phenotype, despite the existence of other mouse models with equivalent mtDNA mutagenic propensity.

Progeria is not a clinical feature of mitochondrial disease patients either, even in those with high amounts of mtDNA mutations. Rather, the phenotype of the mtDNA Mutator mice is remarkably similar to that of other mouse progeria models and human progeric syndromes with nuclear genome instability, with the most prominent defects in proliferating cells, and especially in stem and progenitor cells important for tissue regeneration.

In the present study the researchers show that the Mutator mice show nuclear DNA defects in their stem and progenitor cells. These defects include nuclear genome replication fork stalling, increased DNA-breaks and activation of DNA damage response pathways.

So how can a primary mitochondrial DNA maintenance defect affect maintenance of nuclear genome? The authors showed that mtDNA replication had increased to several fold. This was accompanied by sequestering of DNA building blocks, dNTPs, into mitochondria, and causing lack of dNTPs for nuclear genome maintenance, slowed down replication and DNA damage.

The study presents a new view on how mitochondrial dysfunction can affect cellular nucleotide pools, compromise nuclear genome maintenance and contribute to aging. Ultimately the evidence argues that the contribution of mitochondrial DNA mutations to aging still remains to be defined.