Loss of the Parkinson's disease-linked gene DJ-1 perturbs mitochondrial dynamics

被引:299
作者
Irrcher, I.
Aleyasin, H.
Seifert, E. L. [2 ]
Hewitt, S. J.
Chhabra, S.
Phillips, M.
Lutz, A. K. [4 ]
Rousseaux, M. W. C.
Bevilacqua, L. [2 ]
Jahani-Asl, A.
Callaghan, S.
MacLaurin, J. G.
Winklhofer, K. F. [4 ]
Rizzu, P. [5 ]
Rippstein, P. [3 ]
Kim, R. H. [6 ]
Chen, C. X. [7 ]
Fon, E. A. [7 ]
Slack, R. S.
Harper, M. E. [2 ]
McBride, H. M. [3 ]
Mak, T. W. [6 ]
Park, D. S. [1 ,8 ]
机构
[1] Univ Ottawa, Fac Med, Dept Cellular & Mol Sci, Ottawa, ON K1H 8M5, Canada
[2] Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON K1H 8M5, Canada
[3] Univ Ottawa, Ottawa Heart Inst, Ottawa, ON K1H 8M5, Canada
[4] Univ Munich, Adolf Butenandt Inst, Munich, Germany
[5] Med Genom VU Univ, Med Ctr, Dept Clin Genet, Amsterdam, Netherlands
[6] Univ Toronto, Campbell Family Inst Breast Canc Res, Toronto, ON M5G 2M9, Canada
[7] McGill Univ, Dept Biochem, Montreal, PQ H3A 1A1, Canada
[8] Pusan Natl Univ, Dept Cogno Mechatron Engn, Pusan 609735, South Korea
基金
加拿大健康研究院;
关键词
OXIDATIVE STRESS; CELL-DEATH; PINK1/PARKIN PATHWAY; SKELETAL-MUSCLE; PROTEIN DJ-1; PINK1; AUTOPHAGY; FISSION; DYSFUNCTION; NEURONS;
D O I
10.1093/hmg/ddq288
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Growing evidence highlights a role for mitochondrial dysfunction and oxidative stress as underlying contributors to Parkinson's disease (PD) pathogenesis. DJ-1 (PARK7) is a recently identified recessive familial PD gene. Its loss leads to increased susceptibility of neurons to oxidative stress and death. However, its mechanism of action is not fully understood. Presently, we report that DJ-1 deficiency in cell lines, cultured neurons, mouse brain and lymphoblast cells derived from DJ-1 patients display aberrant mitochondrial morphology. We also show that these DJ-1-dependent mitochondrial defects contribute to oxidative stress-induced sensitivity to cell death since reversal of this fragmented mitochondrial phenotype abrogates neuronal cell death. Reactive oxygen species (ROS) appear to play a critical role in the observed defects, as ROS scavengers rescue the phenotype and mitochondria isolated from DJ-1 deficient animals produce more ROS compared with control. Importantly, the aberrant mitochondrial phenotype can be rescued by the expression of Pink1 and Parkin, two PD-linked genes involved in regulating mitochondrial dynamics and quality control. Finally, we show that DJ-1 deficiency leads to altered autophagy in murine and human cells. Our findings define a mechanism by which the DJ-1-dependent mitochondrial defects contribute to the increased sensitivity to oxidative stress-induced cell death that has been previously reported.
引用
收藏
页码:3734 / 3746
页数:13
相关论文
共 65 条
  • [51] The PINK1/Parkin pathway regulates mitochondrial morphology
    Poole, Angela C.
    Thomas, Ruth E.
    Andrews, Laurie A.
    McBride, Heidi M.
    Whitworth, Alexander J.
    Pallanck, Leo J.
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (05) : 1638 - 1643
  • [52] O-2 SOLUBILITY IN AQUEOUS-MEDIA DETERMINED BY A KINETIC METHOD
    REYNAFARJE, B
    COSTA, LE
    LEHNINGER, AL
    [J]. ANALYTICAL BIOCHEMISTRY, 1985, 145 (02) : 406 - 418
  • [53] In search of an "autophagomometer"
    Rubinsztein, David C.
    Cuervo, Ana Maria
    Ravikumar, Brinda
    Sarkar, Sovan
    Korolchuk, Viktor
    Kaushik, Susmita
    Klionsky, Daniel J.
    [J]. AUTOPHAGY, 2009, 5 (05) : 585 - 589
  • [54] Mitochondrial dysfunction in neurodegenerative disorders
    Schapira, AHV
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS, 1998, 1366 (1-2): : 225 - 233
  • [55] Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4
    Scherz-Shouval, Ruth
    Shvets, Elena
    Fass, Ephraim
    Shorer, Hagai
    Gil, Lidor
    Elazar, Zvulun
    [J]. EMBO JOURNAL, 2007, 26 (07) : 1749 - 1760
  • [56] Essential role for uncoupling protein-3 in mitochondrial adaptation to fasting but not in fatty acid oxidation or fatty acid anion export
    Seifert, Erin L.
    Bezaire, Veronic
    Estey, Carmen
    Harper, Mary-Ellen
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (37) : 25124 - 25131
  • [57] Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism
    Silvestri, L
    Caputo, V
    Bellacchio, E
    Atorino, L
    Dallapiccola, B
    Valente, EM
    Casari, G
    [J]. HUMAN MOLECULAR GENETICS, 2005, 14 (22) : 3477 - 3492
  • [58] DJ-1 has a role in antioxidative stress to prevent cell death
    Taira, T
    Saito, Y
    Niki, T
    Iguchi-Ariga, SMM
    Takahashi, K
    Ariga, H
    [J]. EMBO REPORTS, 2004, 5 (02) : 213 - 218
  • [59] DJ-1/PARK7 is an important mediator of hypoxia-induced cellular responses
    Vasseur, Sophie
    Afzal, Samia
    Tardivel-Lacombe, Joel
    Park, David S.
    Iovanna, Juan Lucio
    Mak, Tak Wah
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (04) : 1111 - 1116
  • [60] PINK1-dependent recruitment of Parkin to mitochondria in mitophagy
    Vives-Bauza, Cristofol
    Zhou, Chun
    Huang, Yong
    Cui, Mei
    de Vries, Rosa L. A.
    Kim, Jiho
    May, Jessica
    Tocilescu, Maja Aleksandra
    Liu, Wencheng
    Ko, Han Seok
    Magrane, Jordi
    Moore, Darren J.
    Dawson, Valina L.
    Grailhe, Regis
    Dawson, Ted M.
    Li, Chenjian
    Tieu, Kim
    Przedborski, Serge
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (01) : 378 - 383