Why can mitochondrial disorders cause different levels of severity in different tissues?

Mitochondrial disorders exhibit varying levels of severity across different tissues primarily due to the random distribution of mitochondria during cell division and the phenomenon of heteroplasmy—the presence of both normal and mutant mitochondrial DNA (mtDNA) within a single cell.12

When a cell divides, mitochondria are distributed randomly to daughter cells. If a cell contains a high percentage of abnormal mitochondria, its ability to produce adenosine triphosphate (ATP) is impaired, leading to cellular dysfunction. Tissues that contain a large proportion of these affected cells will exhibit more severe clinical symptoms.13

The severity of the disease in a specific tissue also depends on the extent of mitochondrial dysfunction and the tissue's specific energy requirements. Because mitochondria are the primary energy-generating apparatus for cells, tissues with high energy demands—such as the brain, muscles, and heart—are often more significantly impacted by mitochondrial failure. Consequently, the clinical presentation of a mitochondrial disorder can range from mild, single-organ involvement to severe, multi-organ failure, depending on the specific distribution of mutant mtDNA and the metabolic needs of the affected organs.132