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The Journal of Neuroscience, January 18, 2006, 26(3):810-820; doi:10.1523/JNEUROSCI.4162-05.2006

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Neurobiology of Disease
Mitochondrial Encephalomyopathy in Drosophila

Alicia M. Celotto,^1,2 Adam C. Frank,^1,2 Steven W. McGrath,^1,2 Tim Fergestad,³ Wayne A. Van Voorhies,⁵ Karolyn F. Buttle,⁴ Carmen A. Mannella,⁴ and Michael J. Palladino^1,2

¹Department of Pharmacology and ²Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, ³Laboratory of Genetics, University of Wisconsin–Madison, Madison, Wisconsin 53706, ⁴Resource for the Visualization of Biological Complexity, Wadsworth Center, New York Department of Health, Albany, New York 12201, and ⁵New Mexico State University, Molecular Biology Program, Las Cruces, New Mexico 88003

Mitochondrial encephalomyopathies are common and devastating multisystem genetic disorders characterized by neuromuscular dysfunction and tissue degeneration. Point mutations in the human mitochondrial ATP6 gene are known to cause several related mitochondrial disorders: NARP (neuropathy, ataxia, and retinitis pigmentosa), MILS (maternally inherited Leigh's syndrome), and FBSN (familial bilateral striatal necrosis). We identified a pathogenic mutation in the Drosophila mitochondrial ATP6 gene that causes progressive, adult-onset neuromuscular dysfunction and myodegeneration. Our results demonstrate ultrastructural defects in the mitochondrial innermembrane, neural dysfunction, and a marked reduction in mitochondrial ATP synthase activity associated with this mutation. This Drosophila mutant recapitulates key features of the human neuromuscular disorders enabling detailed in vivo studies of these enigmatic diseases.

Key words: ATP6; ANT; ATP synthase; neurodegeneration; muscle degeneration; aging; mitochondria

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Received Sep 30, 2005; revised November 22, 2005; accepted November 25, 2005.

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