Mitochondria in age-related disease: the importance of heteroplasmy



Each cell contains numerous energy-producing structures called mitochondria, each with its own mitochondrial genome (mtDNA). As a result, a single cell can contain mitochondria with different genetic variants at the same locations in their individual mtDNA — a phenomenon known as mitochondrial heteroplasmy. While rare mtDNA mutations can lead to a variety of extremely uncommon but severe clinical disorders, mitochondrial genetic variation is also thought to contribute to common age-related cardiometabolic diseases, but the role of heteroplasmy in age-related disease has not been established.


IRP researchers led by Daniel Levy, M.D., sequenced the mtDNA of 356 Framingham Heart Study participants, ultimately identifying 2,880 unique mutations, as well as 11 ‘hot spots’ in the mitochondrial genome where genetic mutations were more common in older individuals. Four of those mutations were predicted to result in the creation of altered mitochondrial proteins, which may directly impact cellular energy production and would likely lead to severe disease if they were present across cellular mitochondria.


This research extended previous findings that healthy individuals carry many low-frequency mitochondrial heteroplasmy mutations with potentially detrimental effects to uncover specific age-related heteroplasmic mutations that are likely to be harmful. While the effect of a single deleterious mtDNA mutation may be minimal, the aggregate effects of many such mutations may cause changes in mitochondrial function that contribute to age-related diseases. The identification of age-related mtDNA mutations is an important step toward understanding the genetic architecture of age-related diseases and may lead to development of novel therapeutic targets for such diseases.


Liu C, Fetterman JL, Liu P, Luo Y, Larson MG, Vasan RS, Zhu J, Levy D. Deep sequencing of the mitochondrial genome reveals common heteroplasmic sites in NADH dehydrogenase genes. (2018). Hum Genet. 137(3):203-213.

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This page was last updated on Friday, June 9, 2023