Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons

• Published in: Nature genetics Vol. 38; no. 5; pp. 518 - 520
• Main Authors: Kraytsberg, Yevgenya, Kudryavtseva, Elena, McKee, Ann C, Geula, Changiz, Kowall, Neil W, Khrapko, Konstantin
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2006; Nature Publishing Group
• Subjects: Aging; Aging - genetics; Agriculture; Animal Genetics and Genomics; Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Brain stem; brief-communication; Cancer Research; Complications and side effects; Cytochrome; Degeneration; DNA damage; DNA, Mitochondrial - genetics; Electron Transport Complex IV - genetics; Fundamental and applied biological sciences. Psychology; Gene Function; Genetic aspects; Genetics of eukaryotes. Biological and molecular evolution; Human Genetics; Human subjects; Mice; Mice, Transgenic; Mitochondrial DNA; Nervous system; Neurons; Neurons - pathology; Parkinson's disease; Physiological aspects; Quantitative genetics; Respiration; Substantia Nigra - pathology; United States; Human; Deletion; Mitochondrial DNA; Neuron; Ageing
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1778

Using a novel single-molecule PCR approach to quantify the total burden of mitochondrial DNA (mtDNA) molecules with deletions, we show that a high proportion of individual pigmented neurons in the aged human substantia nigra contain very high levels of mtDNA deletions. Molecules with deletions are largely clonal within each neuron; that is, they originate from a single deleted mtDNA molecule that has expanded clonally. The fraction of mtDNA deletions is significantly higher in cytochrome c oxidase (COX)-deficient neurons than in COX-positive neurons, suggesting that mtDNA deletions may be directly responsible for impaired cellular respiration.