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

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

doi:10.1016/j.neuron.2013.04.020

Cited by 53 publications

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“…Interestingly, VCP is recruited to damaged mitochondria being involved in their clearance via the PINK1/Parkin pathway. 41 These findings indicate that TG2 might play an important role in mitophagy regulation by its direct interaction with key components of the fission/fusion molecular machinery.…”

Section: Resultsmentioning

confidence: 89%

Transglutaminase 2 ablation leads to mitophagy impairment associated with a metabolic shift towards aerobic glycolysis

et al. 2014

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Macroautophagy selectively degrades dysfunctional mitochondria by a process known as mitophagy. Here we demonstrate the involvement of transglutaminase 2 (TG2) in the turnover and degradation of damaged mitochondria. In TG2-ablated cells we observed the presence of a large number of fragmented mitochondria that display decreased membrane potential, downregulation of IF1 along with increased Drp1 and PINK1 levels, two key proteins regulating the mitochondrial fission. Of note, we demonstrate that in healthy mitochondria, TG2 interacts with the dynamic proteins Drp1 and Fis1; interestingly, their interaction is largely reduced upon induction of the fission process by carbonyl cyanide m-chlorophenyl hydrazine (CCCP). In keeping with these findings, mitochondria lacking TG2 are more susceptible to CCCP treatment. As a consequence of accumulation of damaged mitochondria, cells lacking TG2 increased their aerobic glycolysis and became sensitive to the glycolytic inhibitor 2-deoxy-D-glucose (2-DG). In contrast, TG2-proficient cells are more resistant to 2-DG-induced apoptosis as the caspase 3 is inactivated through the enzyme's crosslinking activity. The data presented in this study show that TG2 plays a key role in cellular dynamics and consequently influences the energetic metabolism.

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Section: Resultsmentioning

confidence: 89%

Transglutaminase 2 ablation leads to mitophagy impairment associated with a metabolic shift towards aerobic glycolysis

et al. 2014

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“…VCP/p97 participates in this pathway through its extraction and degradation of the outer mitochondrial membrane proteins mitofusin-1 and mitofusin-2 following their ubiquitylation by the E3 ligase Parkin (Tanaka et al, 2010). Disease-associated mutations of VCP/p97 abrogate Parkindependent mitophagy (Kim et al, 2013b); however, it is unknown whether a specific defect in mitophagy can explain the Parkinson's phenotype in these particular patients.…”

Section: Box 2 Clinical Syndromes Associated With Vcp Mutationsmentioning

confidence: 99%

The VCP/p97 system at a glance: connecting cellular function to disease pathogenesis

Meyer

Weihl

2014

Journal of Cell Science

359

421

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The ATPase valosin-containing protein (VCP)/p97 has emerged as a central and important element of the ubiquitin system. Together with a network of cofactors, it regulates an ever-expanding range of processes that stretch into almost every aspect of cellular physiology. Its main role in proteostasis and key functions in signaling pathways are of relevance to degenerative diseases and genomic stability. In this Cell Science at a Glance and the accompanying poster, we give a brief overview of this complex system. In addition, we discuss the pathogenic basis for VCP/p97-associated diseases and then highlight in more detail new exciting links to the translational stress response and RNA biology that further underscore the significance of the VCP/p97 system.

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“…In addition to the Pink1/Parkin system, several other proteins (e.g. valosincontaining protein (VCP), the p62 protein, microtubule-associated protein 1 light chain (LC3), the Bcl2/adenovirus E1B 19-kDa protein-interacting protein 3 (Bnip3), the mitochondrial voltage-dependent anion channel (VDAC) and the Nix protein) have been implicated in mitophagy induction, regulation and execution but these are discussed elsewhere [125][126][127][128].…”

Section: Mitochondrial Degradationmentioning

confidence: 99%

Regulation and Quantification of Cellular Mitochondrial Morphology and Content

Tronstad¹,

Nooteboom²,

Nilsson³

et al. 2014

CPD

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Running title: Regulation and quantification of mitochondrial morphology and content. Word count: 15,454 (total)Characters: 107,091 (including spaces); 92,067 (excluding spaces) Keywords: mitochondrial biogenesis, mitochondrial dynamics, mitochondrial degradation, living cells, TMRM, microscopy, segmentation, image analysis.Page 2 of 37 ABSTRACTMitochondria play a key role in signal transduction, redox homeostasis and cell survival, which extends far beyond their classical functioning in ATP production and energy metabolism. In living cells, mitochondrial content ("mitochondrial mass") depends on the cell-controlled balance between mitochondrial biogenesis and degradation. These processes are intricately linked to changes in net mitochondrial morphology and spatiotemporal positioning ("mitochondrial dynamics"), which are governed by mitochondrial fusion, fission and motility. It is becoming increasingly clear that mitochondrial mass and dynamics, as well as its ultrastructure and volume, are mechanistically linked to mitochondrial function and the cell. This means that proper quantification of mitochondrial morphology and content is of prime importance in understanding mitochondrial and cellular physiology in health and disease. This review first presents how cellular mitochondrial content is regulated at the level of mitochondrial biogenesis, degradation and dynamics. Next we discuss how mitochondrial dynamics and content can be analyzed with a special emphasis on quantitative live-cell microscopy strategies.

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

Abstract: In the original Supplemental Information for this Article, the same image was used for both Figure S4 and Figure S5. This has been corrected in the Supplemental Information online.

Cited by 53 publications

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Transglutaminase 2 ablation leads to mitophagy impairment associated with a metabolic shift towards aerobic glycolysis

Transglutaminase 2 ablation leads to mitophagy impairment associated with a metabolic shift towards aerobic glycolysis

The VCP/p97 system at a glance: connecting cellular function to disease pathogenesis

Regulation and Quantification of Cellular Mitochondrial Morphology and Content

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