[Frontiers in Bioscience, Scholar, 7, 109-124, June 1, 2015]

Endangered species: mitochondrial DNA loss as a mechanism of human disease

Alan Herrera 1 , Iraselia Garcia 1 , Norma Gaytan 1 , Edith Jones 1 , Alicia Maldonado 2 , Robert Gilkerson 1, 2

1Departments of Biology and 2Clinical Laboratory Sciences, University of Texas-Pan American, 1201 West University Drive, Edinburg, TX 78539 USA


1. Abstract
2. MtDNA: Composition, copy number and organization
3. Loss of mtDNA across human disease
    3.1. Diabetes and metabolic disease
    3.2. Cardiovascular disease
    3.3. Aging
4. MtDNA mutations: heteroplasmy, threshold effects, and bioenergetic function
    4.1. MtDNA mutations
    4.2. Heteroplasmy and threshold
    4.3. MtDNA depletion syndromes
5. Mechanisms of mtDNA damage and cell-wide effects
    5.1. The network is down: Impacts on organellar structure/function
    5.2. Cell-wide impacts of mtDNA loss: apoptosis and signaling
6. Concluding remarks
7. Acknowledgements
8. References


Human mitochondrial DNA (mtDNA) is a small maternally inherited DNA, typically present in hundreds of copies in a single human cell. Thus, despite its small size, the mitochondrial genome plays a crucial role in the metabolic homeostasis of the cell. Our understanding of mtDNA genotype-phenotype relationships is derived largely from studies of the classical mitochondrial neuromuscular diseases, in which mutations of mtDNA lead to compromised mitochondrial bioenergetic function, with devastating pathological consequences. Emerging research suggests that loss, rather than mutation, of mtDNA plays a major role across a range of prevalent human diseases, including diabetes mellitus, cardiovascular disease, and aging. Here, we examine the ‘rules’ of mitochondrial genetics and function, the clinical settings in which loss of mtDNA is an emerging pathogenic mechanism, and explore mtDNA damage and its consequences for the organellar network and cell at large. As extranuclear genetic material arrayed throughout the cell to support metabolism, mtDNA is increasingly implicated in a host of disease conditions, opening a range of exciting questions regarding mtDNA and its role in cellular homeostasis.


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