Support for mtDNA aging theory

High levels of mitochondrial DNA deletions likely cause respiratory deficiency in aging substantia nigra, two papers say

By | April 10, 2006

Pigmented neurons in aged human substantia nigra -- the main site of neurodegeneration in Parkinson disease -- contain very high levels of mitochondrial DNA (mtDNA) deletions, according to two papers published online this week in Nature Genetics. Neurons with the most mtDNA deletions showed defects in cellular respiration, which the authors say may lead to common symptoms of aging, such as the mild Parkinson-like symptoms often observed in older people. "I think our result in nigra is the most convincing case so far" for the mtDNA mutational theory of aging, Konstantin Khrapko of Harvard Medical School, senior author of one of the papers, told The Scientist. Some evidence has hinted that the substantia nigra might be a good place to look at the effects of mtDNA mutations: Researchers had found that pigmented cells contain high levels of one type of mtDNA deletion, and many of these cells suffer from respiratory deficiency with increasing age. For instance, up to 30% of pigmented neurons in aged brains can be deficient in a major mitochondrial respiratory-chain enzyme called cytochrome c oxidase (COX). Still, these two new papers are the first to link mtDNA deletions to respiratory deficiency on a cell-by-cell basis, said Gino Cortopassi of the University of California, Davis, who did not participate in either study. "That's very exciting." To evaluate the total load of mtDNA deletions in the substantia nigra, Khrapko and his colleagues collected 80 pigmented cells from individuals between 33 and 102 years old. They found significantly more deletions in aged neurons than in young neurons. These aged cells often possessed extremely high levels of deletions -- many showed more than 60% deleted mtDNA, which is considered the phenotypic threshold above which respiratory function of the cell becomes impaired. Working independently, researchers led by Douglass Turnbull of the University of Newcastle upon Tyne, UK, also found very high levels of deleted mtDNA in the substantia nigra of both aged people and people with Parkinson disease. The substantia nigra pigmented cells show "very, very high levels of deleted mtDNA," Turnbull said. "Previous studies in other tissues had reported levels of 0.1-2%, whereas in the substantia nigra neurons it is approaching 50%." To connect these mtDNA deletions with a biochemical deficiency, both groups compared mtDNA deletion levels with COX activity. They found that cells with low COX activity contained significantly more mtDNA deletions than cells with normal COX activity. In Khrapko's study, deletions in all of the COX-deficient neurons exceeded the 60% phenotypic threshold. Both studies are "very convincing," said Giuseppe Attardi of the California Institute of Technology in Pasadena, although they still haven't proven that mtDNA deletions cause COX deficiency. Cortopassi noted that it's impossible to do definitive causal experiments in humans, but "it's really most likely that it's the mutations that are happening first and causing the cytochrome oxidase deficiency, as they both suggest." One-quarter of people over age 65 and half of people older than 85 show mild signs of Parkinson disease, study author Khrapko said in an Email, and these findings suggest that respiratory deficiency in substantia nigra neurons may be the cause. Cells deficient in COX have to rely on glycolysis for energy, which "definitely does not provide enough ATP," Khrapko said. It's also possible that respiratory chain deficiency "could lead to cell death by necrosis or apoptosis," according to Turnbull. Deletions in mtDNA have been tied to COX deficiency in age-related muscle atrophy, Cortopassi said. Researchers have also correlated mtDNA mutations with inactive cells in colon and with "apoptosis, primarily in tissues with rapid cell turnover," Khrapko said, "which can cause anything from hair loss to osteoporosis." But "it's absolutely clear that the substantia nigra is the place where the deletions accumulate to the highest level, not only in the brain, but in the whole body," Cortopassi said. This brain region probably accumulates such high levels of mtDNA deletions because dopamine metabolism produces reactive oxygen species, which then create "a massive amount of oxidative stress," Cortopassi said. "If we're looking for a tissue and a disease in which mitochondrial mutations make a really big difference in aging, this is the place to look." Melissa Lee Phillips Links within this article P. Smaglik, "Parkinson's Disease," The Scientist, November 8, 1999. Y. Kraytsberg et al., "Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons," Nature Genetics, published online April 9, 2006. A. Bender et al., "High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease," Nature Genetics, published online April 9, 2006. C. Holding, "Mitochondrial DNA recombines," The Scientist, May 14, 2004. C.Q. Choi, "How mtDNA mutations cause aging," The Scientist, July 15, 2005. Konstantin Khrapko N.W. Soong et al., "Mosaicism for a specific somatic mitochondrial DNA mutation in adult human brain," Nature Genetics, December 1992. PM_ID: 1303287 K. Itoh et al., "Cytochrome c oxidase defects of the human substantia nigra in normal aging," Neurobiology of Aging, November-December 1996. PM_ID: 9363794 Gino Cortopassi R. Rossignol et al., "Mitochondrial threshold effects," Biochemical Journal, March 15, 2003. PM_ID: 12467494 Douglass Turnbull Giuseppe Attardi D.A. Bennett et al., "Prevalence of parkinsonian signs and associated mortality in a community population of older people," New England Journal of Medicine, January 11, 1996. PM_ID: 8531961

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