DJ-1 Null Dopaminergic Neuronal Cells Exhibit Defects in Mitochondrial Function and Structure: Involvement of Mitochondrial Complex I Assembly

被引:85
作者
Heo, Jun Young [1 ,5 ]
Park, Ji Hoon [1 ]
Kim, Soung Jung [2 ]
Seo, Kang Sik [1 ]
Han, Jeong Su [1 ]
Lee, Sang Hee [3 ]
Kim, Jin Man [3 ]
Park, Jong Il [1 ]
Park, Seung Kiel [1 ]
Lim, Kyu [1 ,5 ]
Hwang, Byung Doo [1 ]
Shong, Minho [2 ]
Kweon, Gi Ryang [1 ,4 ]
机构
[1] Chungnam Natl Univ, Sch Med, Dept Biochem, Taejon, South Korea
[2] Chungnam Natl Univ, Sch Med, Dept Internal Med, Res Ctr Endocrine & Metab Dis, Taejon, South Korea
[3] Chungnam Natl Univ, Sch Med, Dept Pathol, Taejon, South Korea
[4] Chungnam Natl Univ, Sch Med, Res Inst Med Sci, Taejon, South Korea
[5] Chungnam Natl Univ, Sch Med, Infect Signaling Network Res Ctr, Taejon, South Korea
基金
新加坡国家研究基金会;
关键词
PARKINSONS-DISEASE; PROTEIN DJ-1; DYNAMICS; DEFICIENCY; FISSION; GENE; FRAGMENTATION; PATHOGENESIS; AUTOPHAGY; BALANCE;
D O I
10.1371/journal.pone.0032629
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
DJ-1 is a Parkinson's disease-associated gene whose protein product has a protective role in cellular homeostasis by removing cytosolic reactive oxygen species and maintaining mitochondrial function. However, it is not clear how DJ-1 regulates mitochondrial function and why mitochondrial dysfunction is induced by DJ-1 deficiency. In a previous study we showed that DJ-1 null dopaminergic neuronal cells exhibit defective mitochondrial respiratory chain complex I activity. In the present article we investigated the role of DJ-1 in complex I formation by using blue native-polyacrylamide gel electrophoresis and 2-dimensional gel analysis to assess native complex status. On the basis of these experiments, we concluded that DJ-1 null cells have a defect in the assembly of complex I. Concomitant with abnormal complex I formation, DJ-1 null cells show defective supercomplex formation. It is known that aberrant formation of the supercomplex impairs the flow of electrons through the channels between respiratory chain complexes, resulting in mitochondrial dysfunction. We took two approaches to study these mitochondrial defects. The first approach assessed the structural defect by using both confocal microscopy with MitoTracker staining and electron microscopy. The second approach assessed the functional defect by measuring ATP production, O-2 consumption, and mitochondrial membrane potential. Finally, we showed that the assembly defect as well as the structural and functional abnormalities in DJ-1 null cells could be reversed by adenovirus-mediated overexpression of DJ-1, demonstrating the specificity of DJ-1 on these mitochondrial properties. These mitochondrial defects induced by DJ-1mutation may be a pathological mechanism for the degeneration of dopaminergic neurons in Parkinson's disease.
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页数:9
相关论文
共 35 条
[1]   DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase [J].
Andres-Mateos, Eva ;
Perier, Celine ;
Zhang, Li ;
Blanchard-Fillion, Beatrice ;
Greco, Todd M. ;
Thomas, Bobby ;
Ko, Han Seok ;
Sasaki, Masayuki ;
Ischiropoulos, Harry ;
Przedborski, Serge ;
Dawson, Ted M. ;
Dawson, Valina L. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (37) :14807-14812
[2]   Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons [J].
Barsoum, Mark J. ;
Yuan, Hua ;
Gerencser, Akos A. ;
Liot, Geraldine ;
Kushnareva, Yulia E. ;
Graeber, Simone ;
Kovacs, Imre ;
Lee, Wilson D. ;
Waggoner, Jenna ;
Cui, Jiankun ;
White, Andrew D. ;
Bossy, Blaise ;
Martinou, Jean-Claude ;
Youle, Richard J. ;
Lipton, Stuart A. ;
Ellisman, Mark H. ;
Perkins, Guy A. ;
Bossy-Wetzel, Ella .
EMBO JOURNAL, 2006, 25 (16) :3900-3911
[3]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[4]   Mitochondrial dynamics, cell death and the pathogenesis of Parkinson's disease [J].
Bueeler, Hansruedi .
APOPTOSIS, 2010, 15 (11) :1336-1353
[5]   Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson's disease [J].
Bueeler, Hansruedi .
EXPERIMENTAL NEUROLOGY, 2009, 218 (02) :235-246
[6]   Balance is the challenge - The impact of mitochondrial dynamics in Parkinson's disease [J].
Burbulla, Lena F. ;
Krebiehl, Guido ;
Krueger, Rejko .
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, 2010, 40 (11) :1048-1060
[7]   The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila [J].
Deng, Hansong ;
Dodson, Mark W. ;
Huang, Haixia ;
Guo, Ming .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (38) :14503-14508
[8]   Progressive cavitating leukoencephalopathy associated with respiratory chain complex I deficiency and a novel mutation in NDUFS1 [J].
Ferreira, Mariana ;
Torraco, Alessandra ;
Rizza, Teresa ;
Fattori, Fabiana ;
Meschini, Maria Chiara ;
Castana, Cinzia ;
Go, Nancy E. ;
Nargang, Frank E. ;
Duarte, Margarida ;
Piemonte, Fiorella ;
Dionisi-Vici, Carlo ;
Videira, Arnaldo ;
Vilarinho, Laura ;
Santorelli, Filippo M. ;
Carrozzo, Rosalba ;
Bertini, Enrico .
NEUROGENETICS, 2011, 12 (01) :9-17
[9]   Organelle isolation: functional mitochondria from mouse liver, muscle and cultured filroblasts [J].
Frezza, Christian ;
Cipolat, Sara ;
Scorrano, Luca .
NATURE PROTOCOLS, 2007, 2 (02) :287-295
[10]   6-Hydroxydopamine (6-OHDA) induces Drp1-dependent mitochondrial fragmentation in SH-SY5Y cells [J].
Gomez-Lazaro, Maria ;
Bonekamp, Nina A. ;
Galindo, Maria F. ;
Jordan, Joaquin ;
Schrader, Michael .
FREE RADICAL BIOLOGY AND MEDICINE, 2008, 44 (11) :1960-1969