Evidence for Mitochondrial Transfusion to Require Matched Mitochondrial DNA
Researchers here suggest that mixing mitochondrial DNA haplotypes in the same individual has long-term negative consequences to health, though the precise mechanisms by which this happens have yet to be determined. This has the most relevance to ongoing work on mitochondrial transplants as a way to restore mitochondrial function in old people. Fortunately mitochondrial DNA is not completely unique to the individual. There is a large but limited number of haplotypes, so matching to a patient would be more akin to blood type matching for transfusions than having to produce a distinct set of material for each patient. It does raise the question of whether the goal of producing optimized, hyperefficient mitochondria to enhance human capabilities will be as readily achievable as hoped, however.
The presence of more than one mitochondrial DNA (mtDNA) genetic variant in the cell is called heteroplasmy. Although very rare, heteroplasmy sometimes occurs naturally as a result of mtDNA mutations and can cause several diseases. New therapeutic approaches proposed in recent years and aimed at preventing disease or treating infertility can generate a new form of heteroplasmy in people. "This new form of heteroplasmy, involving distinct non-mutated mtDNA variants, is produced when an individual's cells contain both the original recipient mtDNA and the donor mtDNA transferred during the intervention."
Researchers generated mice with a single nuclear genome but with all their cells simultaneously containing two distinct mtDNA variants. This mouse strain was fertile, and young animals showed no related disease. But long-term analysis over the full lifetime of these mice showed that the coexistence of two mtDNA variants in the same cell compromised mitochondrial function. "We observed that cells rejected the presence of two mitochondrial genomes, and most of them progressively eliminated one of the mtDNA variants. Surprisingly, however, major organs like the heart, lungs, and skeletal muscle were unable to do this."
Organs that could eliminate one of the mtDNA variants, like the liver, recovered their mitochondrial metabolism and cellular health, but those that could not progressively deteriorated as the animals aged. Thus the animals, which appeared healthy in their youth, in later life suffered from heart failure, pulmonary hypertension, loss of muscle mass, frailty, and premature death. The researchers conclude that the dangerous effects of mitochondrial therapeutic interventions identified in the new study show the need for caution in the selection of the donor mtDNA genotype.