Neuron
Volume 78, Issue 1, 10 April 2013, Pages 65-80
Journal home page for Neuron

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

https://doi.org/10.1016/j.neuron.2013.02.029Get rights and content
Under an Elsevier user license
open archive

Summary

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.

Highlights

► VCP functions downstream of PINK1 in the PINK1/Parkin pathway ► VCP is recruited to mitochondria in response to Parkin-mediated ubiquitination ► VCP and Npl4/Ufd1 are required for clearance of damaged mitochondria ► Disease mutations in VCP impair its ability to support the PINK1/Parkin pathway

Cited by (0)

5

These authors contributed equally to this work