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Why can mitochondrial disorders affect people differently even when they have the same mitochondrial DNA mutation?

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Fluorescent confocal image of HeLa cells with green microtubules outlining cell shapes, red mitochondria, and blue nuclei. — mitochondrion Mitochondria (red) are found throughout the cytoplasm of almost all eukaryotic cells (cell nucleus is shown in blue; cytoskeleton is shown in yellow).

Even when individuals carry the same mitochondrial DNA (mtDNA) mutation, they can experience significantly different symptoms and disease severity due to a phenomenon known as heteroplasmy.123

Heteroplasmy refers to the presence of a mixed population of both normal and mutant mtDNA within a single cell. Because mitochondria are randomly distributed to daughter cells during cell division, the ratio of mutant to normal mitochondria can vary widely between different cells and tissues within the same person.123

The clinical expression of a mitochondrial disorder depends on several factors:

Degree of Heteroplasmy: If a cell contains a high percentage of abnormal mitochondria, its function will be impaired; if the proportion of normal mitochondria is sufficient, the cell may function normally.1
Tissue Energy Requirements: Tissues with high energy demands, such as the nervous and muscular systems, are typically more susceptible to mitochondrial dysfunction.4
Confounding Factors: Variations in disease severity are also influenced by other genetic or environmental factors that interact with the mitochondrial defect.23

Consequently, affected individuals may exhibit a broad spectrum of symptoms, ranging from being asymptomatic or mildly affected to suffering from severe, multi-organ disease.154