Mitochondrial Mutations and Athletic Endurance

A Review of Genetics, Energy, and Training

Abstract

Endurance performance relies on the sustained generation of adenosine triphosphate (ATP) through mitochondrial oxidative phosphorylation in skeletal muscle. Mitochondrial DNA (mtDNA), which encodes essential components of the electron transport chain, plays a critical role in determining mitochondrial efficiency and aerobic capacity. Mutations in mtDNA—ranging from point substitutions to large deletions—can impair ATP production, leading to exercise intolerance in severe cases and more subtle reductions in endurance performance in otherwise healthy individuals. In addition, naturally occurring mtDNA variation, including mitochondrial haplogroups and heteroplasmy, has been associated with interindividual differences in endurance capacity and training responsiveness. This review synthesizes current evidence on the genetic, molecular, and physiological mechanisms linking mtDNA mutations to endurance performance. It further examines how endurance training and environmental factors modulate mitochondrial function through mitochondrial biogenesis, nuclear–mitochondrial signaling, and epigenetic regulation of genes involved in energy metabolism. Advances in sequencing technologies and mitochondrial imaging have provided new insights into mutation burden, mitochondrial ultrastructure, and their relationship to fatigue resistance. Collectively, the literature indicates that mitochondrial genetics establish biological constraints on endurance performance, while training-induced adaptations and epigenetic mechanisms can partially compensate for these constraints. Understanding this interaction has important implications for athletic training, personalized exercise programs, and the early identification of mitochondrial dysfunction.