mtDNA heteroplasmy

mtDNA heteroplasmy is the coexistence of two or more distinct mitochondrial DNA sequences in a cell, tissue, or individual — wild-type mixed with mutant molecules. Heteroplasmy level (percentage of mutant copies) is quantified by next-generation sequencing or droplet digital PCR. A threshold effect governs disease expression: mitochondrial disorders typically require mutant load above 60–90 % before oxidative phosphorylation fails enough to produce symptoms. Sub-clinical levels carry measurable consequences: a 2018 Scientific Reports analysis of 789 Health ABC participants found m.3243A>G heteroplasmy at 0–19 % associated with reduced grip strength, cognition, and arterial stiffness, with a 96 % higher dementia-mortality hazard in the highest versus lowest tertile (HR = 1.96; Tranah et al.). Somatic mutations accumulate with age; a 2026 Nature analysis of ~750,000 whole-genome sequences (Gupta et al.) found a sharp post-60 rise in heteroplasmy with a spectrum consistent with replication errors rather than oxidative damage — revising a long-held assumption. Accumulation is tissue-specific: post-mitotic tissues retain clonal expansions that blood cells dilute more readily (Sanchez-Contreras et al. 2023, eLife). A germline bottleneck during oogenesis (~30–35 segregating units) causes mutant fractions to shift between generations; maternal age independently raises heteroplasmies in offspring (Rebolledo-Jaramillo et al. 2014). Whether somatic accumulation is causal in aging or primarily a biomarker of replication stress remains under investigation.