Parkinson's Disease–Associated Kinase PINK1 Regulates Miro Protein Level and Axonal Transport of Mitochondria
Song Liu,Tomoyo Sawada,Seongsoo Lee,Wendou Yu,George Silverio,Philomena Alapatt,Ivan Millan,Alice Shen,William M. Saxton,Tomoko Kanao,Ryosuke Takahashi,Nobutaka Hattori,Yuzuru Imai,Bingwei Lu +13 more
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TLDR
It is shown that PINK1 also controls mitochondrial motility and works together with hParkin and Miro in mitochondrial transport and mitophagy, contributing to the understanding of the complex interplays in mitochondrial quality control that are critically involved in PD pathogenesis.Abstract:
Mutations in Pten-induced kinase 1 (PINK1) are linked to early-onset familial Parkinson's disease (FPD). PINK1 has previously been implicated in mitochondrial fission/fusion dynamics, quality control, and electron transport chain function. However, it is not clear how these processes are interconnected and whether they are sufficient to explain all aspects of PINK1 pathogenesis. Here we show that PINK1 also controls mitochondrial motility. In Drosophila, downregulation of dMiro or other components of the mitochondrial transport machinery rescued dPINK1 mutant phenotypes in the muscle and dopaminergic (DA) neurons, whereas dMiro overexpression alone caused DA neuron loss. dMiro protein level was increased in dPINK1 mutant but decreased in dPINK1 or dParkin overexpression conditions. In Drosophila larval motor neurons, overexpression of dPINK1 inhibited axonal mitochondria transport in both anterograde and retrograde directions, whereas dPINK1 knockdown promoted anterograde transport. In HeLa cells, overexpressed hPINK1 worked together with hParkin, another FPD gene, to regulate the ubiquitination and degradation of hMiro1 and hMiro2, apparently in a Ser-156 phosphorylation-independent manner. Also in HeLa cells, loss of hMiro promoted the perinuclear clustering of mitochondria and facilitated autophagy of damaged mitochondria, effects previously associated with activation of the PINK1/Parkin pathway. These newly identified functions of PINK1/Parkin and Miro in mitochondrial transport and mitophagy contribute to our understanding of the complex interplays in mitochondrial quality control that are critically involved in PD pathogenesis, and they may explain the peripheral neuropathy symptoms seen in some PD patients carrying particular PINK1 or Parkin mutations. Moreover, the different effects of loss of PINK1 function on Miro protein level in Drosophila and mouse cells may offer one explanation of the distinct phenotypic manifestations of PINK1 mutants in these two species.read more
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The Roles of PINK1, Parkin and Mitochondrial Fidelity in Parkinson's Disease
TL;DR: Biochemical and genetic studies reveal that the products of two genes that are mutated in autosomal recessive parkinsonism, PINK1 and Parkin, normally work together in the same pathway to govern mitochondrial quality control, bolstering previous evidence that mitochondrial damage is involved in Parkinson's disease.
Journal ArticleDOI
Synaptic Energy Use and Supply
TL;DR: This work describes how information transmission through presynaptic terminals and postsynaptic spines is related to their energy consumption, and assess which mechanisms normally ensure an adequate supply of ATP to these structures.
Journal ArticleDOI
Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization
Shireen A. Sarraf,Malavika Raman,Virginia Guarani-Pereira,Mathew E. Sowa,Edward L. Huttlin,Steven P. Gygi,J. Wade Harper +6 more
TL;DR: Structural and topological analysis revealed extensive conservation of PARKIN-dependent ubiquitylation sites on cytoplasmic domains in vertebrate and Drosophila melanogaster MOM proteins, providing a resource for understanding how the PINK1–PARKIN pathway re-sculpts the proteome to support mitochondrial homeostasis.
Journal ArticleDOI
PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65
Chandana Kondapalli,Agne Kazlauskaite,Ning Zhang,Helen I. Woodroof,David G. Campbell,Robert Gourlay,Lynn Burchell,Helen Walden,Thomas Macartney,Maria Deak,Axel Knebel,Dario R. Alessi,Miratul M. K. Muqit +12 more
TL;DR: These results provide the first evidence that PINK1 is activated following Δψm depolarization and suggest that Pink1 directly phosphorylates and activates Parkin, and indicate that monitoring phosphorylation of Parkin at Ser65 and/or Pinks1 at Thr257 represent the first biomarkers for examining activity of the PINK 1-Parkin signalling pathway in vivo.
Journal ArticleDOI
Mitochondrial dynamics and mitochondrial quality control.
TL;DR: This review discusses the most recent progress on the molecular mechanisms and roles of mitochondrial fission/fusion and mitochondrial motility in mitophagy, and discusses multiple pathways leading to the quality control of mitochondria in addition to the traditionalMitophagy pathway under different conditions.
References
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Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism
Tohru Kitada,Shuichi Asakawa,Nobutaka Hattori,Hiroto Matsumine,Yasuhiro Yamamura,Shinsei Minoshima,Masayuki Yokochi,Yoshikuni Mizuno,Nobuyoshi Shimizu +8 more
TL;DR: Mutations in the newly identified gene appear to be responsible for the pathogenesis of Autosomal recessive juvenile parkinsonism, and the protein product is named ‘Parkin’.
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
Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1
Eriza Maria Valente,Patrick M. Abou-Sleiman,Viviana Caputo,Miratul M. K. Muqit,Kirsten Harvey,Suzana Gispert,Zeeshan Ali,Domenico Del Turco,Anna Rita Bentivoglio,Daniel G. Healy,Alberto Albanese,Robert L. Nussbaum,Rafael González-Maldonado,Thomas Deller,S Salvi,Pietro Cortelli,William P. Gilks,David S. Latchman,Roberk J. Harvey,Bruno Dallapiccola,Georg Auburger,Nicholas W. Wood +21 more
TL;DR: The identification of two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families provide a direct molecular link between mitochondria and the pathogenesis of PD.
Journal ArticleDOI
Mechanisms of mitophagy
TL;DR: Mitophagy, the specific autophagic elimination of mitochondria, has been identified in yeast, and in mammals during red blood cell differentiation, mediated by NIP3-like protein X (NIX; also known as BNIP3L).
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.