Single-cell and cybrid (cytoplasmic hybrid) studies have shown that the proportion of mutated mtDNA is directly related to the expression of a biochemical defect within the cell. There is a critical ratio between wildtype and mutant mtDNA that must be exceeded before phenotypic expression of the disease occurs. For the majority of mtDNA mutations this percentage mutation load threshold correlates with the histochemically demonstratable activity of cytochrome c oxidase (COX, complex IV of the respiratory chain). Above the mutation threshold cells appear COX negative, while at lower mutation loads COX activity can still be demonstrated. The threshold level is variable and dependent on the type of mutation and its location, with some tRNA mutations requiring 85% mutant mtDNA while some protein coding mutations and deletions can express a mutant phenotype at much lower levels. Although the percentage level of mutated mtDNA appears to be important, for most mutations it is not clear whether the respiratory chain defect is actually due to the ratio of mutated to wild-type mtDNA, or related to the absolute amount of wildtype mtDNA (analogous to haplo-insuffiency), or mutated mtDNA (through a dominant negative effect).
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