Abstract
Rare genetic mutations in the DJ-1 and Parkin genes cause recessive Parkinsonism, however, the relationship between these two genes is not fully elucidated. Current emerging evidence suggests that these genes are involved in mitochondrial homeostasis, and that a deficiency in either of these two genes is associated with damages in mitochondrial function and morphology. In this study, we demonstrated that knockdown of DJ-1 expression or the overexpression of the DJ-1 L166P mutation results in a damaged phenotype in mitochondria and a hypersensitivity to H2O2-induced cell apoptosis. These phenotypes result from increased levels of endogenous oxidative stress. However, overexpression of wild-type Parkin rescued the phenotypes observed in the mitochondria of DJ-1 knockdown and DJ-1 L166P mutant cells. We also determined that there were differences between the two cell models. Furthermore, both H2O2 treatment and the DJ-1 L166P mutation weakened the interaction between DJ-1 and Parkin. Taken together, these findings suggested that DJ-1 and Parkin were linked through oxidative stress, and that overexpression of Parkin protects DJ-1 protein-deficient and DJ-1 L166P mutant-expressing cells via inhibition of oxidative stress.
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Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:256–259
Batelli S, Albani D, Rametta R, Polito L, Prato F, Pesaresi M, Negro A, Forloni G (2008) DJ-1 modulates alpha-synuclein aggregation state in a cellular model of oxidative stress: relevance for Parkinson’s disease and involvement of HSP70. PLoS One 3:e1884
Zhou W, Freed CR (2005) DJ-1 up-regulates glutathione synthesis during oxidative stress and inhibits A53T alpha-synuclein toxicity. J Biol Chem 280:43150–43158
Clements CM, McNally RS, Conti BJ, Mak TW, Ting JP (2006) DJ-1, a cancer- and Parkinson’s disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc Natl Acad Sci USA 103:15091–15096
Im JY, Lee KW, Junn E, Mouradian MM (2010) DJ-1 protects against oxidative damage by regulating the thioredoxin/ASK1 complex. Neurosci Res 67:203–208
Mo JS, Kim MY, Ann EJ, Hong JA, Park HS (2008) DJ-1 modulates UV-induced oxidative stress signaling through the suppression of MEKK1 and cell death. Cell Death Differ 15:1030–1041
Wang Z, Liu J, Chen S, Wang Y, Cao L (2011) DJ-1 modulates the expression of Cu/Zn-superoxide dismutase-1 through the Erk1/2-Elk1 pathway in neuroprotection. Ann Neurol 70:591–599
Clements CM, McNally RS, Conti BJ, Mak TW, Ting JP (2006) DJ-1, a cancer- and Parkinson’s disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc Natl Acad Sci USA 103:15091–15096
Zhong N, Xu J (2008) Synergistic activation of the human MnSOD promoter by DJ-1 and PGC-1 alpha: regulation by SUMOylation and oxidation. Hum Mol Genet 17:3357–3367
Thomas KJ, McCoy MK, Blackinton J, Beilina A, van der Brug M, Sandebring A, Miller D, Maric D, Cedazo-Minguez A, Cookson MR (2011) DJ-1 acts in parallel to the PINK1/parkin pathway to control mitochondrial function and autophagy. Hum Mol Genet 20:40–50
Meulener M, Whitworth AJ, Armstrong-Gold CE, Rizzu P, Heutink P, Wes PD, Pallanck LJ, Bonini NM (2005) Drosophila DJ-1 mutants are selectively sensitive to environmental toxins associated with Parkinson’s disease. Curr Biol 15:1572–1577
Flinn L, Mortiboys H, Volkmann K, Koster RW, Ingham PW, Bandmann O (2009) Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio). Brain 132:1613–1623
Rothfuss O, Fischer H, Hasegawa T, Maisel M, Leitner P, Miesel F, Sharma M, Bornemann A, Berg D, Gasser T, Patenge N (2009) Parkin protects mitochondrial genome integrity and supports mitochondrial DNA repair. Hum Mol Genet 18:3832–3850
Poole AC, Thomas RE, Andrews LA, McBride HM, Whitworth AJ, Pallanck LJ (2008) The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci USA 105:1638–1643
Mortiboys H, Thomas KJ, Koopman WJ, Klaffke S, Abou-Sleiman P, Olpin S, Wood NW, Willems PH, Smeitink JA, Cookson MR, Bandmann O (2008) Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts. Ann Neurol 64:555–565
Joselin AP, Hewitt SJ, Callaghan SM, Kim RH, Chung YH, Mak TW, Shen J, Slack RS, Park DS (2012) ROS-dependent regulation of Parkin and DJ-1 localization during oxidative stress in neurons. Hum Mol Genet 21:4888–4903
Zucchelli S, Vilotti S, Calligaris R, Lavina ZS, Biagioli M, Foti R, De Maso L, Pinto M, Gorza M, Speretta E, Casseler C, Tell G, Del Sal G, Gustincich S (2009) Aggresome-forming TTRAP mediates pro-apoptotic properties of Parkinson’s disease-associated DJ-1 missense mutations. Cell Death Differ 16:428–438
Bandopadhyay R, Kingsbury AE, Cookson MR, Reid AR, Evans IM, Hope AD, Pittman AM, Lashley T, Canet-Aviles R, Miller DW, McLendon C, Strand C, Leonard AJ, Abou-Sleiman PM, Healy DG, Ariga H, Wood NW, de Silva R, Revesz T, Hardy JA, Lees AJ (2004) The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson’s disease. Brain 127:420–430
Junn E, Jang WH, Zhao X, Jeong BS, Mouradian MM (2009) Mitochondrial localization of DJ-1 leads to enhanced neuroprotection. J Neurosci Res 87:123–129
Moore DJ, Zhang L, Dawson TM, Dawson VL (2003) A missense mutation (L166P) in DJ-1, linked to familial Parkinson’s disease, confers reduced protein stability and impairs homo-oligomerization. J Neurochem 87:1558–1567
Alvarez-Castelao B, Munoz C, Sanchez I, Goethals M, Vandekerckhove J, Castano JG (2012) Reduced protein stability of human DJ-1/PARK7 L166P, linked to autosomal recessive Parkinson disease, is due to direct endoproteolytic cleavage by the proteasome. Biochim Biophys Acta 1823:524–533
Ren H, Fu K, Mu C, Zhen X, Wang G (2012) L166P mutant DJ-1 promotes cell death by dissociating Bax from mitochondrial Bcl-XL. Mol Neurodegener 7:40–51
Hayashi T, Ishimori C, Takahashi-Niki K, Taira T, Kim YC, Maita H, Maita C, Ariga H, Iguchi-Ariga SM (2009) DJ-1 binds to mitochondrial complex I and maintains its activity. Biochem Biophys Res Commun 390:667–672
Heo JY, Park JH, Kim SJ, Seo KS, Han JS, Lee SH, Kim JM, Park JI, Park SK, Lim K, Hwang BD, Shong M, Kweon GR (2012) DJ-1 null dopaminergic neuronal cells exhibit defects in mitochondrial function and structure: involvement of mitochondrial complex I assembly. PLoS One 7:e32629
Kwon HJ, Heo JY, Shim JH, Park JH, Seo KS, Ryu MJ, Han JS, Shong M, Son JH, Kweon GR (2011) DJ-1 mediates paraquat-induced dopaminergic neuronal cell death. Toxicol Lett 202:85–92
Wang X, Petrie TG, Liu Y, Liu J, Fujioka H, Zhu X (2012) Parkinson’s disease-associated DJ-1 mutations impair mitochondrial dynamics and cause mitochondrial dysfunction. J Neurochem 121:830–839
Berger AK, Cortese GP, Amodeo KD, Weihofen A, Letai A, LaVoie MJ (2009) Parkin selectively alters the intrinsic threshold for mitochondrial cytochrome c release. Hum Mol Genet 18:4317–4328
Yu W, Sun Y, Guo S, Lu B (2011) The PINK1/Parkin pathway regulates mitochondrial dynamics and function in mammalian hippocampal and dopaminergic neurons. Hum Mol Genet 20:3227–3240
Wang H, Song P, Du L, Tian W, Yue W, Liu M, Li D, Wang B, Zhu Y, Cao C, Zhou J, Chen Q (2011) Parkin ubiquitinates Drp1 for proteasome-dependent degradation: implication of dysregulated mitochondrial dynamics in Parkinson disease. J Biol Chem 286:11649–11658
Glauser L, Sonnay S, Stafa K, Moore DJ (2011) Parkin promotes the ubiquitination and degradation of the mitochondrial fusion factor mitofusin 1. J Neurochem 118:636–645
Gegg ME, Schapira AH (2011) PINK1-parkin-dependent mitophagy involves ubiquitination of mitofusins 1 and 2: implications for Parkinson disease pathogenesis. Autophagy 7:243–245
Vives-Bauza C, Zhou C, Huang Y, Cui M, de Vries RL, Kim J, May J, Tocilescu MA, Liu W, Ko HS, Magrane J, Moore DJ, Dawson VL, Grailhe R, Dawson TM, Li C, Tieu K, Przedborski S (2010) PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci USA 107:378–383
Hao LY, Giasson BI, Bonini NM (2010) DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function. Proc Natl Acad Sci USA 107:9747–9752
Xiong H, Wang D, Chen L, Choo YS, Ma H, Tang C, Xia K, Jiang W, Ronai Z, Zhuang X, Zhang Z (2009) Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation. J Clin Invest 119:650–660
Acknowledgments
This study was supported by grants obtained from the Doctoral Program of Higher Education of China (Grant No. 20100071110036), the Shanghai Municipal Natural Science Foundation, China (Grant No. 10ZR1403200), and Basic Research Project of Shanghai Science and Technology Commission (13JC1401101).
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Chang, C., Wu, G., Gao, P. et al. Upregulated Parkin expression protects mitochondrial homeostasis in DJ-1 konckdown cells and cells overexpressing the DJ-1 L166P mutation. Mol Cell Biochem 387, 187–195 (2014). https://doi.org/10.1007/s11010-013-1884-3
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DOI: https://doi.org/10.1007/s11010-013-1884-3