heteroplasmy

Heteroplasmy is the presence of more than one type of mitochondrial DNA (mtDNA) within a cell or individual. Because each mitochondrion contains multiple copies of mtDNA and cells harbor many mitochondria, a cell can carry a mixture of wild-type and mutated genomes. When all mtDNA copies are identical, the cell is said to be homoplasmic; when different variants coexist, it is heteroplasmic.

Most pathogenic mtDNA mutations are heteroplasmic, and disease expression depends on the proportion of mutant genomes, known as the heteroplasmy level, as well as the tissue involved. A higher mutant load often increases the likelihood and severity of symptoms, but the relationship is variable and mutation-specific. Some tissues, especially those with high energy demands like muscle and brain, are more sensitive to mutant mtDNA.

Inheritance of mtDNA is predominantly maternal. During oogenesis, a genetic bottleneck can cause rapid shifts in heteroplasmy between generations, so offspring may have markedly different mutant loads despite sharing the same mother. In individuals, heteroplasmy levels vary among tissues and can change over time due to cell division and selective replication of mtDNA genomes.

Detection and measurement of heteroplasmy rely on sequencing-based methods, quantitative PCR, or digital PCR to estimate the percentage of mtDNA copies carrying a mutation. Reporting typically includes the heteroplasmy level and the specific mutation, with interpretation often dependent on tissue sampled.

Examples of clinically relevant heteroplasmic mtDNA mutations include certain point mutations associated with MELAS and MERRF syndromes, and large deletions linked to other mitochondrial disorders. Understanding heteroplasmy is central to diagnosis, prognosis, and research into mitochondrial disease mechanisms.