Mitochondria: Biogenesis and mitophagy balance in segregation and clonal expansion of mitochondrial DNA mutations |
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Affiliation: | 1. INSERM U1051, Institut des Neurosciences de Montpellier, Université de Montpellier, Montpellier 34091, France;2. Karolinska Institutet, Department of Clinical Neuroscience, Department of Neuroscience, Stockhom 171 77, Sweden;3. Mitochondrial Medicine Research Centre, Pôle de Recherche et d''Enseignement en Médecine Mitochondriale, Université d''Angers, Angers 49933, France;2. Cell Stress Group, MRC London Institute of Medical Sciences (LMS), London, United Kingdom;3. Biotechnology in Animal Production, Department for Agrobiotechnology, IFA Tulln, Tulln, Austria;1. Department of Environmental Health, University of Cincinnati College of Medicine, 160 Panzeca Way, Cincinnati, OH 45267, United States;2. Department of Developmental Neurobiology, National Institute of Perinatology, Montes Urales 800, Lomas Virreyes, Mexico City 11000, Mexico;3. Department of Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, United States;4. Department of Statistics, Colorado State University, Fort Collins, CO, United States;5. Department of Biostatistics, Harvard T.H. Chan School of Public Health, 655 Huntington Ave., Boston, MA 02115, United States;6. Department of Geography and Environmental Development, Ben-Gurion University of the Negev, P.O.B 653, Beer Sheva, Israel;7. Department of Environmental Health, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA 02115, United States;8. Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University Medical Center, 722 W 168th St., New York, NY 10032, United States;9. Department of Psychiatry, Boston Children''s Hospital, 300 Longwood Ave., Boston, MA 02215, United States;10. Department of Psychiatry, Harvard Medical School, 401 Park Dr., Boston, MA 02215, United States;11. Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, 17 East 102nd St., New York, NY 10029, United States;12. Institute for Exposomic Research, Icahn School of Medicine at Mount Sinai, 17 East 102nd St., New York, NY 10029, United States |
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Abstract: | Mitochondria are cytoplasmic organelles containing their own multi-copy genome. They are organized in a highly dynamic network, resulting from balance between fission and fusion, which maintains homeostasis of mitochondrial mass through mitochondrial biogenesis and mitophagy. Mitochondrial DNA (mtDNA) mutates much faster than nuclear DNA. In particular, mtDNA point mutations and deletions may occur somatically and accumulate with aging, coexisting with the wild type, a condition known as heteroplasmy. Under specific circumstances, clonal expansion of mutant mtDNA may occur within single cells, causing a wide range of severe human diseases when mutant overcomes wild type. Furthermore, mtDNA deletions accumulate and clonally expand as a consequence of deleterious mutations in nuclear genes involved in mtDNA replication and maintenance, as well as in mitochondrial fusion genes (mitofusin-2 and OPA1), possibly implicating mtDNA nucleoids segregation. We here discuss how the intricacies of mitochondrial homeostasis impinge on the intracellular propagation of mutant mtDNA.This article is part of a Directed Issue entitled: Energy Metabolism Disorders and Therapies. |
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Keywords: | Mitochondrial DNA Mitochondrial DNA mutations Clonal expansion Mitophagy Nucleoids |
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