Human mitochondrial DNA variants influence telomere length: evidence from a transmitochondrial cybrid model
Abstract
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 telomere lengths into mtDNA-depleted cells. This revealed an inverse correlation between donor blood TL and mitochondrial ROS levels measured in the resulting cybrids. Under the specific conditions of cybrid formation, which involve a metabolic shift from glycolysis to oxidative phosphorylation, mtDNA variants associated with reduced complex I (CI) activity induced rapid telomere shortening, further implicating mitochondrial metabolism in TL regulation. Notably, this effect was prevented by antioxidant treatment and supplementation with NAD⁺ precursors, supporting a critical role for CI in sustaining PARP1 activity through maintenance of the NAD⁺/NADH balance to preserve telomere integrity under acute oxidative stress. Collectively, these findings suggest that specific mtDNA variants may contribute to the maintenance of long telomeres in humans by enhancing mitochondrial fitness, thereby highlighting potential therapeutic opportunities for mitochondrial replacement strategies.
Significance Statement
Telomere length at birth influences aging trajectories and disease risk later in life, yet the mechanisms governing this trait remain incompletely understood. Using a transmitochondrial cybrid approach, we show that single-nucleotide variants in the mitochondrial genome of healthy donors directly affect mitochondrial metabolism and reactive oxygen species production. In addition, mitochondrial ROS levels measured in cybrids inversely correlate with blood cell telomere length in donors. Mitochondrial DNA variants associated with reduced complex I activity promote telomere shortening during an i n vitro metabolic shift toward oxidative phosphorylation, an effect that is reversed by antioxidant treatment or NAD⁺ precursor supplementation. Together, these findings establish a direct link between mitochondrial genetics, redox homeostasis, and telomere maintenance in human cells.
Related articles
Related articles are currently not available for this article.