Common Principles Underlie Mitochondrial DNA Heteroplasmy Dynamics in the Germline and Soma

Heteroplasmy is the mixture of mutant and wild-type mitochondrial DNA (mtDNA) within each of our cells. Heteroplasmy levels in cells, tissues, and organisms change over time, thus contributing to mitochondrial disease, aging, and evolution. Germline and pedigree studies first revealed heteroplasmy shifts between generations and have long offered a window into the dynamics of mtDNA inheritance through single oocytes. Single-cell technologies are now uncovering similar mechanisms that operate in somatic tissues throughout life. Stochastic processes (relaxed replication and vegetative segregation, enhanced through genetic bottlenecks) generate cell-to-cell variation, while selection mechanisms such as intercellular competition, mitophagy, and preferential replication allow or drive directional shifts. Single-cell sequencing, mtDNA imaging, and genetic screening, combined with mtDNA-editing technology and heteroplasmic model systems, have transformed our ability to dissect these processes, revealing heteroplasmy dynamics at molecular resolution. These approaches are uncovering quantifiable principles governing heteroplasmy across cell types and life stages, transforming our understanding from descriptive observations to predictive mechanistic models and novel therapeutic avenues.