Several lines of research have led to the theory that mitochondrial DNA (mtDNA) damage directly contributes to ageing by leading to respiratory chain defects that result in increased production of reactive oxygen species, causing various types of cellular damage. Now in Nature Metabolism, Hämäläinen et al. challenge this view, reporting that mtDNA replication defects might cause ageing indirectly by inducing nuclear DNA replication stress.

Credit: V. Summersby/Springer Nature Limited

The study was based on the previous observation that in mutator mice — a mouse model of premature ageing — which accumulate high levels of mtDNA mutations, oxidative damage is not increased; moreover, respiratory chain deficiency is not typically associated with premature ageing.

As aberrant somatic stem cell pool functions play a key part in the premature ageing of mutator mice, the authors went on to analyse the ROS-independent mechanisms underlying this defect.

Mutator mouse-derived induced pluripotent stem cells (iPSCs) showed signs of replication stress — cells accumulated in late G1/early S phase and nuclear DNA replication was slowed down owing to replication fork stalling, which is indicative of DNA damage. Consistently, accumulation of double-strand DNA (dsDNA) breaks and activation of the ATM and ATR–CHK1 DNA damage response pathways were observed. Nuclear DNA damage was confirmed in vivo, in mutator male gamete precursor cells. Together, these observations indicate that mtDNA damage has a negative effect on nuclear genome maintenance.

So how might mtDNA damage affect nuclear DNA replication? Normally, cellular levels of dNTP increase in preparation for S phase and remain high until DNA replication is completed. But in mutator iPSCs, whole-cell dNTP pools were depleted whereas mitochondrial dNTP pools were enriched, suggesting that following mtDNA damage, cellular dNTPs are sequestered into mitochondria to enhance mtDNA replication. The resulting dNTP depletion in the nucleus would lead to nuclear DNA damage. Indeed, slowing down mtDNA replication reduced the accumulation of dsDNA breaks and improved genome stability.

mtDNA damage has a negative effect on nuclear genome maintenance

This study presents a new view of how mitochondrial dysfunction might contribute to ageing, by linking increased mtDNA replication to nuclear DNA replication stress and genome instability — another hallmark of ageing.