ALT Maintenance of mtDNA heteroplasmy in iPSCs. Generation of iPSC lines from patient cells with mtDNA mutations can result in a shift in heteroplasmy from the somatic cell levels in either direction, although biased toward loss of mutant load. Similarly, heteroplasmy can shift in either direction as heteroplasmic iPSC lines (orange cells) are passaged, with a general bias towards a decreased mutant load over time (green cells, lower mutant load; red cells, higher mutant load). During directed differentiation, heteroplasmy is typically unchanged from the level observed in the undifferentiated iPSCs. However, during teratoma assays, different cell lineages can end up manifesting cell‐type specific oxidative phosphorylation defects that may depend on the specific mtDNA mutation. These biases appear to be selective, with mechanisms such as genetic bottleneck and genetic drift only playing a minor role. Created with BioRender.com.