Mahieu, M.; Defour, J.-P.; Mathieu, B.; Richiardone, E.; Heremans, I.; Levy, G.; Le Berre, G.; Scheers, I.; Brichard, B.; Arnould, T.; Bommer, G.; Gallez, B.; Corbet, C.; Decottignies, A.

Telomere shortening is a hallmark of aging, yet telomere length (TL) varies considerably among individuals and is strongly influenced by inheritance. In mice, efficient mitochondrial function -characterized by low reactive oxygen species (ROS) production- is critical for telomere elongation during early embryogenesis. Since mitochondrial DNA (mtDNA) encodes several subunits of the electron transport chain, it may influence TL at birth by regulating mitochondrial function in utero. To explore the relationship between mtDNA and TL, we used a transmitochondrial cybrid approach, introducing mitochondria from donor platelets with varying TLs into mtDNA-depleted cells. This revealed an inverse correlation between donor blood TL and mitochondrial ROS levels in the resulting cybrids. Under the specific experimental conditions of cybrid formation, characterized by a metabolic shift from glycolysis to oxidative phosphorylation, mtDNA variants linked to lower complex I activity triggered rapid telomere shortening, further implicating mitochondrial metabolism in TL regulation. Notably, this effect was prevented by antioxidant treatment and NAD+ precursor supplementation. Collectively, these findings establish a connection between the mitochondrial genome and human TL, and highlight the pivotal role of complex I in supporting NAD+ metabolism and preserving telomere integrity under oxidative stress.