VCP Is Essential for Mitochondrial Quality Control by PINK1/Parkin and this Function Is Impaired by VCP Mutations

Nam Chul Kim, Emilie Tresse, Regina Maria Kolaitis, Amandine Molliex, Ruth E. Thomas, Nael H. Alami, Bo Wang, Aashish Joshi, Rebecca B. Smith, Gillian P. Ritson, Brett J. Winborn, Jennifer Moore, Joo Yong Lee, Tso Pang Yao, Leo Pallanck, Mondira Kundu, J. Paul Taylor

Research output: Contribution to journalArticlepeer-review

185 Scopus citations


Mutations in VCP cause multisystem degeneration impacting the nervous system, muscle, and/or bone. Patients may present with ALS, Parkinsonism, frontotemporal dementia, myopathy, Paget@s disease, or a combination of these. The disease mechanism is unknown. We developed a Drosophila model of VCP mutation-dependent degeneration. The phenotype is reminiscent of PINK1 and parkin mutants, including a pronounced mitochondrial defect. Indeed, VCP interacts genetically with the PINK1/parkin pathway in vivo. Paradoxically, VCP complements PINK1 deficiency but not parkin deficiency. The basis of this paradox is resolved by mechanistic studies in vitro showing that VCP recruitment to damaged mitochondria requires Parkin-mediated ubiquitination of mitochondrial targets. VCP recruitment coincides temporally with mitochondrial fission, and VCP is required for proteasome-dependent degradation of Mitofusins in vitro and in vivo. Further, VCP and its adaptor Npl4/Ufd1 are required for clearance of damaged mitochondria via the PINK1/Parkin pathway, and this is impaired by pathogenic mutations in VCP

Original languageEnglish (US)
Pages (from-to)65-80
Number of pages16
Issue number1
StatePublished - Apr 10 2013

Bibliographical note

Funding Information:
We thank the Hartwell Center for Bioinformatics and Biotechnology and the Cell and Tissue Imaging Core Facility at St. Jude Children’s Research Hospital. We thank Fabien Llambi and Doug Green for the mito-Cerulean plasmid and Richard Youle for YFP-Parkin stable HeLa cells. Financial support was provided NIH grant NS-054022 to T.P.Y., NIH grant GM086394 to L.P., and by NIH grant AG031587, a grant for The Robert Packard Foundation for ALS Research at Johns Hopkins, and support from American-Lebanese-Syrian Associated Charities (ALSAC) to J.P.T.


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