Epigenetic Mechanisms of Mitochondrial Retrograde Signaling and Telomere Maintenance

Mitochondrial DNA (MtDNA) damage is common to myriad of human diseases. Although transcriptional reprograming and telomere defects are hallmarks of these pathologies, currently it is not clear how mitochondrial dysfunction plays a role in telomere defects.  Reduced MtDNA copy number induces mitochondria-to-nucleus retrograde signaling (MtRS) causing global change in nuclear gene expression.  Here we show that MtRS plays a causal role in telomere shortening, telomerase activation and telomere H4K8 acetylation. These processes are aborted when MtDNA content is reversed to near normal cell levels.  We show that the mitochondrial stress induced coactivator, heterogeneous ribonucleoprotein (hnRNP) A2 has intrinsic histone acetyltransferase (HAT) activity with K8 of H4 (H4K8) as its target. HnRNPA2 residues Arg48 and Arg50 are crucial for its HAT activity. HnRNPA2 mediated H4K8 acetylation at the mitochondrial stress-responsive promoters and telomere DNA is critical for both gene expression and telomere attrition.  We therefore describe a novel epigenetic mechanism for MtRS-induced gene expression and telomere loss using mouse and human cells and also MPV17 (-/-) mice which show reduced mtDNA content.