Mutations in cytochrome c oxidase subunit VIa cause neurodegeneration and motor dysfunction in Drosophila.
Mitochondrial dysfunction is involved in many neurodegenerative disorders in humans. Here we report mutations in a gene (designated levy) that codes for subunit VIa of cytochrome c oxidase (COX). The mutations were identified by the phenotype of temperature-induced paralysis and showed the additional phenotypes of decreased COX activity, age-dependent bang-induced paralysis, progressive neurodegeneration, and reduced life span. Germ-line transformation using the levy(+) gene rescued the mutant flies from all phenotypes including neurodegeneration. The data from levy mutants reveal a COX-mediated pathway in Drosophila, disruption of which leads to mitochondrial encephalomyopathic effects including neurodegeneration, motor dysfunction, and premature death. The data present the first case of a mutation in a nuclear-encoded structural subunit of COX that causes mitochondrial encephalomyopathy rather than lethality, whereas several previous attempts to identify such mutations have not been successful. The levy mutants provide a genetic model to understand the mechanisms underlying COX-mediated mitochondrial encephalomyopathies and to explore possible therapeutic interventions.
Liu
Wensheng
W
Department of Pharmacology and Toxicology, State University of New York, Buffalo, New York 14260, USA.
Gnanasambandam
Radhakrishnan
R
Benjamin
Jeffery
J
Kaur
Gunisha
G
Getman
Patricia B
PB
Siegel
Alan J
AJ
Shortridge
Randall D
RD
Singh
Satpal
S
D000818:Animals; D002950:Citrate (si)-Synthase / Q000235:genetics; D004330:Drosophila / Q000201:enzymology / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000378:metabolism*; D018095:Germ-Line Mutation; D006801:Humans; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics; D009043:Motor Activity / Q000235:genetics*; D016296:Mutagenesis; D009410:Nerve Degeneration / Q000235:genetics*; D010243:Paralysis / Q000235:genetics; D010641:Phenotype
D003576:Electron Transport Complex IV; D002950:Citrate (si)-Synthase