Mitochondrial Disease variation in healthy older adults: a genotype-phenotype assessment linking pathogenic variants and mitochondrial constraint

Mitochondrial diseases (MDs) are caused by variants in the mitochondrial (mtDNA) or nuclear (nDNA) genome and encompass a diverse disease spectrum, whilst mitochondrial dysfunction more broadly is implicated in aging and neurodegeneration, with distinct and overlapping phenotypic features. Recent population genomic studies reveal pathogenic MD variation to be common in the population and somatic mtDNA variants accumulate from the seventh decade. Cumulative burden of mtDNA variation, quantified using mitochondrial genome constraint measures, may mediate mitochondrial dysfunction generally. However, the clinical relevance of incidentally identified variation for MDs, and of mitochondrial const