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The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila

Deng, Hansong and Dodson, Mark W. and Huang, Haixia and Guo, Ming (2008) The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila. Proceedings of the National Academy of Sciences of the United States of America, 105 (38). pp. 14503-14508. ISSN 0027-8424. PMCID PMC2567186. doi:10.1073/pnas.0803998105. https://resolver.caltech.edu/CaltechAUTHORS:DENpnas08

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Abstract

Mutations in PTEN-induced kinase 1 (pink1) or parkin cause autosomal-recessive and some sporadic forms of Parkinson's disease. pink1 acts upstream of parkin in a common genetic pathway to regulate mitochondrial integrity in Drosophila. Mitochondrial morphology is maintained by a dynamic balance between the opposing actions of mitochondrial fusion, controlled by Mitofusin (mfn) and Optic atrophy 1 (opa1), and mitochondrial fission, controlled by drp1. Here, we explore interactions between pink1/parkin and the mitochondrial fusion/fission machinery. Muscle-specific knockdown of the fly homologue of Mfn (Marf) or opa1, or overexpression of drp1, results in significant mitochondrial fragmentation. Mfn-knockdown flies also display altered cristae morphology. Interestingly, knockdown of Mfn or opa1 or overexpression of drp1, rescues the phenotypes of muscle degeneration, cell death, and mitochondrial abnormalities in pink1 or parkin mutants. In the male germline, we also observe genetic interactions between pink1 and the testes-specific mfn homologue fuzzy onion, and between pink1 and drp1. Our data suggest that the pink1/parkin pathway promotes mitochondrial fission and/or inhibits fusion by negatively regulating mfn and opa1 function, and/or positively regulating drp1. However, pink1 and parkin mutant flies show distinct mitochondrial phenotypes from drp1 mutant flies, and flies carrying a heterozygous mutation in drp1 enhance the pink1-null phenotype, resulting in lethality. These results suggest that pink1 and parkin are likely not core components of the drp1-mediated mitochondrial fission machinery. Modification of fusion and fission may represent a novel therapeutic strategy for Parkinson's disease.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.0803998105DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc2567186/PubMed CentralArticle
Additional Information:© 2008 by The National Academy of Sciences of the USA. Edited by Douglas C. Wallace, University of California Irvine College of Medicine, Irvine, CA, and accepted by the Editorial Board July 30, 2008 (received for review April 25, 2008). This article is a PNAS Direct Submission. Published online before print September 17, 2008, doi: 10.1073/pnas.0803998105. Note. While this article was in review, Yang et al. published a report (Proc Natl Acad Sci USA 105:7070–7075) suggesting that pink1 interacts with drp1, fis1, and opa1, findings that are consistent with this work. We thank G. Mohiddin Lone for generating one construct; Margaret Fuller, Hugo Bellen, and Leo Pallanck for fly stocks; Frank Laski for his microtome; Bruce Hay for comments on the manuscript; and the Guo lab members for discussions. This work was supported by the a National Institute of Health NRSA predoctoral fellowship (to M.W.D.), National Institute of Health Grants K02 and R01 (to M.G.), the Alfred P. Sloan Foundation, American Parkinson’s Disease Association, Glenn Family Foundation, and the McKnight Endowment Fund for Neuroscience (to M.G.). Author contributions: H.D., M.W.D., and M.G. designed research; H.D. and M.W.D. performed research; H.D., M.W.D., and M.G. analyzed data; H.H. contributed new reagents/analytic tools; and M.G. wrote the paper. The authors declare no conflict of interest. This article contains supporting information online at www.pnas.org/cgi/content/full/0803998105/DCSupplemental.
Funders:
Funding AgencyGrant Number
NIH Predoctoral FellowshipUNSPECIFIED
Alfred P. Sloan FoundationUNSPECIFIED
American Parkinson's Disease AssociationUNSPECIFIED
Glenn Family FoundationUNSPECIFIED
McKnight Endowment Fund for NeuroscienceUNSPECIFIED
Subject Keywords:mitofusin; drp1; opa1; parkin-pink1
Issue or Number:38
PubMed Central ID:PMC2567186
DOI:10.1073/pnas.0803998105
Record Number:CaltechAUTHORS:DENpnas08
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:DENpnas08
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:11744
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:22 Sep 2008 21:26
Last Modified:08 Nov 2021 22:02

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