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Expression of Yeast NDI1 Rescues a Drosophila Complex I Assembly Defect

Cho, Jaehyoung and Hur, Jae H. and Graniel, Jacqueline and Benzer, Seymour and Walker, David W. (2012) Expression of Yeast NDI1 Rescues a Drosophila Complex I Assembly Defect. PLoS ONE, 7 (11). Art. No. e50644. ISSN 1932-6203. PMCID PMC3511326. doi:10.1371/journal.pone.0050644.

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Defects in mitochondrial electron transport chain (ETC) function have been implicated in a number of neurodegenerative disorders, cancer, and aging. Mitochondrial complex I (NADH dehydrogenase) is the largest and most complicated enzyme of the ETC with 45 subunits originating from two separate genomes. The biogenesis of complex I is an intricate process that requires multiple steps, subassemblies, and assembly factors. Here, we report the generation and characterization of a Drosophila model of complex I assembly factor deficiency. We show that CG7598 (dCIA30), the Drosophila homolog of human complex I assembly factor Ndufaf1, is necessary for proper complex I assembly. Reduced expression of dCIA30 results in the loss of the complex I holoenzyme band in blue-native polyacrylamide gel electrophoresis and loss of NADH:ubiquinone oxidoreductase activity in isolated mitochondria. The complex I assembly defect, caused by mutation or RNAi of dCIA30, has repercussions both during development and adulthood in Drosophila, including developmental arrest at the pupal stage and reduced stress resistance during adulthood. Expression of the single-subunit yeast alternative NADH dehydrogenase, Ndi1, can partially or wholly rescue phenotypes associated with the complex I assembly defect. Our work shows that CG7598/dCIA30 is a functional homolog of Ndufaf1 and adds to the accumulating evidence that transgenic NDI1 expression is a viable therapy for disorders arising from complex I deficiency.

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Additional Information:© 2012 Cho 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. Received: July 4, 2012; Accepted: October 23, 2012; Published: November 30, 2012. DWW is funded by National Institutes of Health/National Institute on Aging (grant numbers RO1 AG037514 and R01AG040288). DWW is also an Ellison Medical Foundation New Scholar in Aging (grant number AG-NS-0470-08). SB was funded by the National Institutes of Health/National Institute on Aging (grant numbers RO1 DK070154 and RO1 AG024366). JG is funded by the National Institutes of Health/National Institute of General Medical Sciences (grant number NIH MARC T34 GM008563). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We dedicate this work to the inspiring life and career of our friend and mentor Seymour Benzer. We thank Rosalind Young for help with Electron Microscopy. We thank the Bloomington Drosophila Stock Center and Vienna Drosophila RNAi Center for fly stocks. Author Contributions: Conceived and designed the experiments: JC JHH SB DWW. Performed the experiments: JC JHH JG. Analyzed the data: JC JHH JG DWW. Wrote the paper: JC JHH DWW.
Funding AgencyGrant Number
NIHRO1 AG037514
Ellison Medical FoundationAG-NS-0470-08
NIHRO1 DK070154
NIHRO1 AG024366
NIH Predoctoral FellowshipT34 GM008563
Issue or Number:11
PubMed Central ID:PMC3511326
Record Number:CaltechAUTHORS:20130201-101329815
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Official Citation:Cho J, Hur JH, Graniel J, Benzer S, Walker DW (2012) Expression of Yeast NDI1 Rescues a Drosophila Complex I Assembly Defect. PLoS ONE 7(11): e50644. doi:10.1371/journal.pone.0050644
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:36733
Deposited By: Jason Perez
Deposited On:04 Feb 2013 18:48
Last Modified:09 Nov 2021 23:24

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