The mitochondrial genome is an independent genetic system in each eukaryotic cell outside the nuclear genome. While most researchers tend to overlook it because of its small size, the mitochondrial genome contains genes that are essential for cellular energetics and survival . Because of the increased awareness on the importance of metabolism and bioenergetics in a wide variety of human diseases, more and more mitochondrial DNA sequencing studies are performed to study the link between mtDNA sequence variation and disease development. Mitochondrial genome-wide association studies have established the connection between mtDNA and a wide variety of diseases such as cancer, autoimmune, and neurodegenerative disorders such as Alzheimer’s and Parkinson’s. The close tie between mtDNA and cellular metabolic state also arises from the fact that mtDNA is highly subject to mutagenic attacks from reactive oxygen species released from the electron transport chain, leading to accumulation of somatic mutations. This, coupled with the very limited DNA damage repair capability in the organelle, leads to sequence alterations in mtDNA at a much higher frequency than that in the nuclear DNA. As each mitochondrion contains 2-10 copies of mtDNA and each cell contains hundreds to thousands copies, the presence of heterogeneous mtDNA sequences, due to different mutations in different copies, results in a condition called heteroplasmy. Increased levels of mtDNA heteroplasmy, as an indicator of cellular metabolic dysfunction, in turn leads to elevated metabolic abnormality due to amino acid coding change in key oxidative phosphorylation proteins. This vicious cycle is the basis of an increasing list of human diseases.
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