How can mitochondrial DNA mutations lead to inherited disorders?

Mitochondrial DNA (mtDNA) mutations lead to inherited disorders through a unique process known as maternal (mitochondrial) inheritance. Because mitochondria are located in the cytoplasm of the ovum, they are passed exclusively from mothers to all of their children; spermatozoa do not contribute mitochondria to the developing embryo.12

These mutations compromise the function of the mitochondrion, specifically impairing the production of adenosine triphosphate (ATP), which is the primary energy source for cells. The severity of these disorders is influenced by heteroplasmy—the presence of a mixture of both normal and mutant mtDNA within a single cell. If a cell contains a significant percentage of abnormal mitochondria, the resulting tissue exhibits impaired function.321

Because mitochondria are randomly distributed during cell division, the clinical presentation of these disorders varies widely, ranging from mild, single-organ involvement to severe, multi-organ failure. While some conditions are caused by mtDNA mutations, it is important to note that the majority of mitochondrial diseases actually result from mutations in nuclear genes that encode proteins essential for mitochondrial function.142