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

Abstract

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.

Mitochondrial quality control in the myocardium: Cooperation between protein degradation and mitophagy

“…In addition, the AAA ATPase VCP/p97 extracts ubiquitinated proteins from multimeric complexes or structures for recycling or degradation by the proteasome [15]. VCP recruitment to damaged mitochondria is dependent on Parkin [16]. Ubiquitination of certain proteins by Parkin allows for p62 binding and subsequent removal of the entire organelle via autophagy [11].…”

Mitochondrial quality control: Easy come, easy go

“…Those organelles which are quiescent, inefficient at ATP production or producing high levels of reactive oxygen species (ROS) combine to contribute to an extremely heterogeneous network. Impaired mitochondrial quality control results in accumulation of damaged mitochondria that may release more reactive oxygen species [8], produce less ATP [9], have a lower threshold for cytochrome c release resulting in apoptosis [10], undergo mitochondrial permeability transition pore (MPTP) opening resulting in necrosis [11], or may release mitochondrial components (mtHSP60, oxidized mitochondrial DNA) into cytosol where its recognition by receptors for damage-associated molecular patterns (DAMP) activates inflammation [12]. Mitochondrial turnover is therefore an integral aspect of quality control in which dysfunctional mitochondria are selectively eliminated through autophagy (mitophagy) and replaced through expansion of preexisting mitochondria (biogenesis) [13].…”

RNA metabolism in the pathogenesis of Parkinson׳s disease

“…Parkin may directly ubiquitinate and promote the degradation of the mitochondrial fusion regulator Mfn (or Marf in Drosophila ), thereby inhibiting mitochondrial fusion (Ziviani et al, 2010), or it may positively regulate the fission regulators Drp1 and Fis1. Interestingly, a recent study implicated the valosin-containing protein (VCP) gene in the regulation of mitochondrial dynamics by the PINK1/Parkin pathway (Kim et al, 2013). VCP interacts genetically with the PINK1/parkin pathway in vivo , and VCP recruitment to damaged mitochondria requires Parkin-mediated ubiquitination of mitochondrial targets.…”