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The yeast complex I equivalent NADH dehydrogenase rescues pink1 mutants

Vilain, S; Esposito, G; Haddad, D; Schaap, O; Dobreva, MP; Vos, M; Van Meensel, S; ... Verstreken, P; + view all (2012) The yeast complex I equivalent NADH dehydrogenase rescues pink1 mutants. PLoS Genetics , 8 (1) , Article e1002456. 10.1371/journal.pgen.1002456. Green open access

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Abstract

Pink1 is a mitochondrial kinase involved in Parkinson's disease, and loss of Pink1 function affects mitochondrial morphology via a pathway involving Parkin and components of the mitochondrial remodeling machinery. Pink1 loss also affects the enzymatic activity of isolated Complex I of the electron transport chain (ETC); however, the primary defect in pink1 mutants is unclear. We tested the hypothesis that ETC deficiency is upstream of other pink1-associated phenotypes. We expressed Saccaromyces cerevisiae Ndi1p, an enzyme that bypasses ETC Complex I, or sea squirt Ciona intestinalis AOX, an enzyme that bypasses ETC Complex III and IV, in pink1 mutant Drosophila and find that expression of Ndi1p, but not of AOX, rescues pink1-associated defects. Likewise, loss of function of subunits that encode for Complex I-associated proteins displays many of the pink1-associated phenotypes, and these defects are rescued by Ndi1p expression. Conversely, expression of Ndi1p fails to rescue any of the parkin mutant phenotypes. Additionally, unlike pink1 mutants, fly parkin mutants do not show reduced enzymatic activity of Complex I, indicating that Ndi1p acts downstream or parallel to Pink1, but upstream or independent of Parkin. Furthermore, while increasing mitochondrial fission or decreasing mitochondrial fusion rescues mitochondrial morphological defects in pink1 mutants, these manipulations fail to significantly rescue the reduced enzymatic activity of Complex I, indicating that functional defects observed at the level of Complex I enzymatic activity in pink1 mutant mitochondria do not arise from morphological defects. Our data indicate a central role for Complex I dysfunction in pink1-associated defects, and our genetic analyses with heterologous ETC enzymes suggest that Ndi1p-dependent NADH dehydrogenase activity largely acts downstream of, or in parallel to, Pink1 but upstream of Parkin and mitochondrial remodeling.

Type: Article
Title: The yeast complex I equivalent NADH dehydrogenase rescues pink1 mutants
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pgen.1002456
Publisher version: http://dx.doi.org/10.1371/journal.pgen.1002456
Language: English
Additional information: © 2012 Vilain et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PMCID: PMC3252300
Keywords: Animals, Genetically Modified, Ciona intestinalis, Cytoskeletal Proteins, Drosophila Proteins, Drosophila melanogaster, Electron Transport Complex I, Electron Transport Complex III, Electron Transport Complex IV, GTP-Binding Proteins, Gene Expression Regulation, Humans, Male, Membrane Proteins, Mitochondria, Mitochondrial Proteins, Mutation, Oxidoreductases, Parkinson Disease, Plant Proteins, Protein-Serine-Threonine Kinases, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Ubiquitin-Protein Ligases
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UK Dementia Research Institute HQ
URI: https://discovery.ucl.ac.uk/id/eprint/1408584
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