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


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.

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Figure 1: Fraction of deleted mtDNA in individual pigmented neurons of substantia nigra from subjects of different ages.
Figure 2: Clonal expansions of mtDNA deletions are associated with COX defects in individual neurons.


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The authors are grateful to A. Griner, A. Kraytsberg, and A. Vaysburd for help in experiments; E. Richfield (Rutgers University) for tissue samples and critical review of the manuscript; W. Kunz for communicating his histochemistry protocols and O. Kocher (Beth Israel Deaconess Medical Center) for granting access to a laser capture microscope. This work was supported in part by US National Institutes of Health grants ES11343 and AG19787 to K.K. and AG13846 (Boston University Alzheimer Disease Center) to N.W.K. and the Department of Veteran Affairs.

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Correspondence to Konstantin Khrapko.

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Kraytsberg, Y., Kudryavtseva, E., McKee, A. et al. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet 38, 518–520 (2006).

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