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Dis Model Mech. 2014 Oct;7(10):1165-74. doi: 10.1242/dmm.015321. Epub 2014 Aug 1.

A Drosophila model of mitochondrial disease caused by a complex I mutation that uncouples proton pumping from electron transfer.

Author information

1
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
2
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
3
Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA 98101, USA.
4
Department of Pathology, University of Washington, Seattle, WA 98195, USA.
5
Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA 98101, USA. pgm4@uw.edu pallanck@uw.edu.
6
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. pgm4@uw.edu pallanck@uw.edu.

Abstract

Mutations affecting mitochondrial complex I, a multi-subunit assembly that couples electron transfer to proton pumping, are the most frequent cause of heritable mitochondrial diseases. However, the mechanisms by which complex I dysfunction results in disease remain unclear. Here, we describe a Drosophila model of complex I deficiency caused by a homoplasmic mutation in the mitochondrial-DNA-encoded NADH dehydrogenase subunit 2 (ND2) gene. We show that ND2 mutants exhibit phenotypes that resemble symptoms of mitochondrial disease, including shortened lifespan, progressive neurodegeneration, diminished neural mitochondrial membrane potential and lower levels of neural ATP. Our biochemical studies of ND2 mutants reveal that complex I is unable to efficiently couple electron transfer to proton pumping. Thus, our study provides evidence that the ND2 subunit participates directly in the proton pumping mechanism of complex I. Together, our findings support the model that diminished respiratory chain activity, and consequent energy deficiency, are responsible for the pathogenesis of complex-I-associated neurodegeneration.

KEYWORDS:

Drosophila; Leigh syndrome; Mitochondria; Mitochondrial disease; Neurodegeneration; Respiratory chain

PMID:
25085991
PMCID:
PMC4174527
DOI:
10.1242/dmm.015321
[Indexed for MEDLINE]
Free PMC Article

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