Different dynamic movements of wild‐type and pathogenic VCPs and their cofactors to damaged mitochondria in a Parkin‐mediated mitochondrial quality control system
Yoko Kimura,Junpei Fukushi,Seiji Hori,Noriyuki Matsuda,Kei Okatsu,Kei Okatsu,Yukie Kakiyama,Junko Kawawaki,Akira Kakizuka,Keiji Tanaka +9 more
TLDR
Exogenous expression of wild‐type VCP, but not pathogenic VCPs, reduces the number of abnormal mitochondria in muscles in adult flies, and these results suggest that the increased affinities of pathogenicVCPs for these cofactors cause the impaired movement of Pathogenic V CPs.Abstract:
VCP/p97 is a hexameric ring-shaped AAA(+) ATPase that participates in various ubiquitin-associated cellular functions. Mis-sense mutations in VCP gene are associated with the pathogenesis of two inherited diseases: inclusion body myopathy associated with Paget's disease of the bone and front-temporal dementia (IBMPFD) and familial amyotrophic lateral sclerosis (ALS). These pathogenic VCPs have higher affinities for several cofactors, including Npl4, Ufd1 and p47. In Parkin-dependent mitochondrial quality control systems, VCP migrates to damaged mitochondria (e.g., those treated with uncouplers) to aid in the degradation of mitochondrial outer membrane proteins and to eliminate mitochondria. We showed that endogenous Npl4 and p47 also migrate to mitochondria after uncoupler treatment, and Npl4, Ufd1 or p47 silencing causes defective mitochondria clearance after uncoupler treatment. Moreover, pathogenic VCPs show impaired migration to mitochondria, and the exogenous pathogenic VCP expression partially inhibits Npl4 and p47 localization to mitochondria. These results suggest that the increased affinities of pathogenic VCPs for these cofactors cause the impaired movement of pathogenic VCPs. In adult flies, exogenous expression of wild-type VCP, but not pathogenic VCPs, reduces the number of abnormal mitochondria in muscles. Failure of pathogenic VCPs to function on damaged mitochondria may be related to the pathogenesis of IBMPFD and ALS.read more
Citations
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Journal ArticleDOI
Mfn2 ubiquitination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy
Gian-Luca McLelland,Thomas Goiran,Wei Yi,Geneviève Dorval,Carol X.-Q. Chen,Nadine D Lauinger,Andrea I Krahn,Sepideh Valimehr,Aleksandar Rakovic,Isabelle Rouiller,Thomas M. Durcan,Jean-François Trempe,Edward A. Fon +12 more
TL;DR: The mechanism by which Mfn2, a mitochondria-ER tether, gates the autophagic turnover of mitochondria by PINK1 and parkin is described, which suppresses mitophagy and describes a parkin-/PINK1-dependent mechanism that regulates the destruction of mitochondrial-ER contact sites.
Journal ArticleDOI
The ubiquitin signal and autophagy: an orchestrated dance leading to mitochondrial degradation
TL;DR: This review highlights the current understanding of the detailed molecular mechanisms governing Parkin‐/Pink1‐mediated mitophagy and the evidences connecting Parkin/PINK1 function and mitochondrial clearance in neurons.
Journal ArticleDOI
Ubiquitination and the Regulation of Membrane Proteins.
TL;DR: The mechanisms and functions of ubiquitination of membrane proteins are summarized and specific examples of Ubiquitin-dependent regulation of membrane Protein Regulation are provided to downregulate the physiological outcomes.
Journal ArticleDOI
Structure and function of the AAA+ ATPase p97/Cdc48p.
Di Xia,Wai Kwan Tang,Yihong Ye +2 more
TL;DR: This review summarizes the current understanding of the structure and function of this essential cellular chaperoning system.
Journal ArticleDOI
A Mighty "Protein Extractor" of the Cell: Structure and Function of the p97/CDC48 ATPase.
TL;DR: The current understanding of the structure and function of this important cellular machinery is summarized and the relevant clinical implications are discussed.
References
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Journal ArticleDOI
Parkin is recruited selectively to impaired mitochondria and promotes their autophagy
TL;DR: It is shown that Parkin is selectively recruited to dysfunctional mitochondria with low membrane potential in mammalian cells and this recruitment promotes autophagy of damaged mitochondria and implicate a failure to eliminate dysfunctional mitochondira in the pathogenesis of Parkinson's disease.
Journal ArticleDOI
PINK1 is selectively stabilized on impaired mitochondria to activate Parkin.
Derek P. Narendra,Seok Min Jin,Atsushi Tanaka,Der-Fen Suen,Clement A. Gautier,Jie Shen,Mark R. Cookson,Richard J. Youle +7 more
TL;DR: The authors suggest that PINK1 and Parkin form a pathway that senses damaged mitochondria and selectively targets them for degradation.
Journal ArticleDOI
PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy
Noriyuki Matsuda,Shigeto Sato,Kahori Shiba,Kei Okatsu,Keiko Saisho,Clement A. Gautier,Yu-shin Sou,Shinji Saiki,Sumihiro Kawajiri,Fumiaki Sato,Mayumi Kimura,Masaaki Komatsu,Nobutaka Hattori,Keiji Tanaka +13 more
TL;DR: Defective mitochondrial quality control is shown to be a mechanism for neurodegeneration in some forms of Parkinson's disease.
Journal ArticleDOI
PINK1-dependent recruitment of Parkin to mitochondria in mitophagy
Cristofol Vives-Bauza,Chun Zhou,Yong Huang,Mei Cui,Rosa L.A. de Vries,Jiho Kim,Jessica May,Maja Aleksandra Tocilescu,Wencheng Liu,Han Seok Ko,Jordi Magrané,Darren J. Moore,Darren J. Moore,Valina L. Dawson,Regis Grailhe,Ted M. Dawson,Chenjian Li,Kim Tieu,Serge Przedborski +18 more
TL;DR: It is suggested that Parkin, together with PINK1, modulates mitochondrial trafficking, especially to the perinuclear region, a subcellular area associated with autophagy, which may alter mitochondrial turnover which, in turn, may cause the accumulation of defective mitochondria and, ultimately, neurodegeneration in Parkinson's disease.
Journal ArticleDOI
Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.
Giles D. J. Watts,Jill Wymer,Margaret J. Kovach,Sarju G. Mehta,Steven Mumm,Daniel Darvish,Alan Pestronk,Michael P. Whyte,Virginia Kimonis +8 more
TL;DR: Identification of VCP as causing IBMPFD has important implications for other inclusion-body diseases, including myopathies, dementias and Paget disease of bone (PDB), as it may define a new common pathological ubiquitin-based pathway.
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