MITOCHONDRIAL DNA HETEROPLASMY IN DISEASE: DIAGNOSTIC CHALLENGES AND EMERGING THERAPEUTIC STRATEGIES

Abstract

Mitochondrial DNA differs fundamentally from nuclear DNA in that pathogenic mutations frequently exist in a heteroplasmic state, meaning that wild-type and mutated mitochondrial genomes coexist within the same cell, tissue, and individual, with the proportion of mutated to wild-type molecules varying considerably between different organs of a single patient and even between family members carrying the identical mutation. Clinical disease manifestation typically follows a threshold effect, in which biochemical and clinical symptoms emerge only once the proportion of mutated mitochondrial DNA within an affected tissue exceeds a critical level, a property that produces the strikingly variable clinical phenotypes observed even among carriers of the same underlying mutation [1].