Abstract
Mitochondrial quality control and clearance of damaged mitochondria through mitophagy are important cellular activities. Studies have shown that PTEN-induced putative protein kinase 1 (PINK1) and Parkin play central roles in triggering mitophagy; however, little is known regarding the mechanism by which PINK1 modulates mitophagy in response to reactive oxygen species (ROS)-induced stress. In this study, chlorpyrifos (CPF)-induced ROS caused mitochondrial damage and subsequent engulfing of mitochondria in double-membrane autophagic vesicles, indicating that clearance of damaged mitochondria is due to mitophagy. CPF treatment resulted in PINK1 stabilization on the outer mitochondrial membrane and subsequently increased Parkin recruitment from the cytosol to the abnormal mitochondria. We found that PINK1 physically interacts with Parkin in the mitochondria of CPF-treated cells. Furthermore, a knockdown of PINK1 strongly inhibited the LC3-II protein level by blocking Parkin recruitment. This indicates that CPF-induced mitophagy is due to PINK1 stabilization in mitochondria. We observed that PINK1 stabilization was selectively regulated by ROS-mediated c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling activation but not p38 signaling. In the mitochondria of CPF-exposed cells, pretreatment with specific inhibitors of JNK and ERK1/2 significantly decreased PINK1 stabilization and Parkin recruitment and blocked the LC3-II protein level. Specifically, JNK and ERK1/2 inhibition also dramatically blocked the interaction between PINK1 and Parkin. Our results demonstrated that PINK1 regulation plays a critical role in CPF-induced mitophagy. The simple interpretation of these results is that JNK and ERK1/2 signaling regulates PINK1/Parkin-dependent mitophagy in the mitochondria of CPF-treated cells. Overall, this study proposes a novel molecular regulatory mechanism of PINK1 stabilization under CPF exposure.
Similar content being viewed by others
References
Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39:359–407
Gorell JM, Johonson CC, Rybicki BA, Peterson EL, Richardson RJ (1998) The risk of Parkinson’s disease with exposure to pesticides, farming, well water, and rural living. Neurology 50:1346–1350
Huang X, Moir RD, Tanzi RE, Bush AI, Rogers JT (2004) Redox-active metals, oxidative stress, and Alzheimer’s disease pathology. Ann N Y Acad Sci 1012:153–163
Oh-hashi K, Maruyama W, Yi H, Takahashi T, Naoi M, Isobe K (1999) Mitogen-activated protein kinase pathway mediates peroxynitrite-induced apoptosis in human dopaminergic neuroblastoma SH-SY5Y cells. Biochem Biophys Res Commun 263:504–509
Gomez-Santos C, Ferrer I, Reiriz J, Vinals F, Barrachina M, Ambrosio S (2002) MPP+ increases alpha-synuclein expression and ERK/MAP-kinase phosphorylation in human neuroblastoma SH-SY5Y cells. Brain Res 935:32–39
Cheng Y, Qiu F, Tashiro S, Onodera S, Ikejima T (2008) ERK and JNK mediate TNF alpha-induced p53 activation in apoptotic and autophagic L929 cell death. Biochem Biophys Res Commun 376:483–488
Sridharan S, Jain K, Basu A (2011) Regulation of autophagy by kinases. Cancers (Basel) 3:2630–2654
Dagda RK, Zhu J, Kulich SM, Chu CT (2008) Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress: implications for Parkinson’s disease. Autophagy 4:770–782
Mao K, Klionsky DJ (2011) MAPKs regulate mitophagy in Saccharomyces cerevisiae. Autophagy 7:1564–1565
Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795
Goldman SJ, Taylor R, Zhang Y, Jin S (2010) Autophagy and the degradation of mitochondria. Mitochondrion 10:309–315
Kim I, Rodriguez-Enriquez S, Lemasters JJ (2007) Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys 462:245–253
Lemasters JJ (2005) Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res 8:3–5
Youle RJ, Narendra DP (2011) Mechanisms of mitophagy. Nat Rev Mol Cell Biol 12:9–14
Narendra D, Tanaka A, Suen DF, Youle RJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183:795–803
Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ (2010) PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 8, e1000298
Vives-Bauza C, Zhou C, Huang Y, Cui M, de Vries RL, Kim J, May J, Tocilescu MA et al (2010) PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci U S A 107:378–383
Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y et al (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608
Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D et al (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160
Büeler H (2009) Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson’s disease. Exp Neurol 218:235–246
Li H, Guo M (2009) Protein degradation in Parkinson disease revisited: it’s complex. J Clin Invest 119:442–445
Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR, Seol JH, Yoo SJ, Hay BA et al (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441:1162–1166
Park J, Lee SB, Lee S, Kim Y, Song S, Kim S, Bae E, Kim J et al (2006) Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441:1157–1161
Yang Y, Gehrke S, Imai Y, Huang Z, Ouyang Y, Wang JW, Yang L, Beal MF et al (2006) Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proc Natl Acad Sci U S A 103:10793–10798
Meissner C, Lorenz H, Weihofen A, Selkoe DJ, Lemberg MK (2011) The mitochondrial intramembrane protease PARL cleaves human Pink1 to regulate Pink1 trafficking. J Neurochem 117:856–867
Greene AW, Grenier K, Aguileta MA, Muise S, Farazifard R, Haque ME, McBride HM, Park DS et al (2012) Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment. EMBO Rep 13:378–385
Kane LA, Lazarou M, Fogel AI, Li Y, Yamano K, Sarraf SA, Banerjee S, Youle RJ (2014) PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol 205:143–153
Geisler S, Holmström KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, Springer W (2010) PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 12:119–131
Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier CA, Sou YS, Saiki S et al (2010) PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 189:211–221
Lee JY, Nagano Y, Taylor JP, Lim KL, Yao TP (2010) Disease-causing mutations in parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy. J Cell Biol 189:671–679
Dai H, Deng Y, Zhang J, Han H, Zhao M, Li Y, Zhang C, Tian J et al (2015) PINK1/Parkin-mediated mitophagy alleviates chlorpyrifos-induced apoptosis in SH-SY5Y cells. Toxicology 334:72–80
Gegg ME, Cooper JM, Schapira AH, Taanman JW (2009) Silencing of PINK1 expression affects mitochondrial DNA and oxidative phosphorylation in dopaminergic cells. PLoS ONE 4, e4756
Fennessey CM, Ivie SE, McClain MS (2012) Coenzyme depletion by members of the aerolysin family of pore-forming toxins leads to diminished ATP levels and cell death. Mol Biosyst 8:2097–2105
Hefti M, Albert I, Luginbuehl V (2012) Phenytoin reduces 5-aminolevulinic acid-induced protoporphyrin IX accumulation in malignant glioma cells. J Neurooncol 108:443–450
Nair R, Shaha C (2003) Diethylstilbestrol induces rat spermatogenic cell apoptosis in vivo through increased expression of spermatogenic cell Fas/FasL system. J Biol Chem 278:6470–6481
Hwang J, Sato H, Tang Y, Matsuda D, Maquat LE (2010) UPF1 association with the cap-binding protein, CBP80, promotes nonsense-mediated mRNA decay at two distinct steps. Mol Cell 39:396–409
Park JH, Lee JE, Shin IC, Koh HC (2013) Autophagy regulates chlorpyrifos-induced apoptosis in SH-SY5Y cells. Toxicol Appl Pharmacol 268:55–67
Taylor ER, Hurrell F, Shannon RJ, Lin TK, Hirst J, Murphy MP (2003) Reversible glutathionylation of complex I increases mitochondrial superoxide formation. J Biol Chem 278:19603–19610
Liu L, Feng D, Chen G, Chen M, Zheng Q, Song P, Ma Q, Zhu C et al (2012) Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat Cell Biol 14:177–185
Garcia-Garcia A, Anandhan A, Burns M, Chen H, Zhou Y, Franco R (2013) Impairment of Atg5-dependent autophagic flux promotes paraquat- and MPP+-induced apoptosis but not rotenone or 6-hydroxydopamine toxicity. Toxicol Sci 136:166–182
Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI, Thomas-Tikhonenko A, Thompson CB (2007) Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 117:326–336
Ki YW, Lee JE, Park JH, Shin IC, Koh HC (2012) Reactive oxygen species and mitogen-activated protein kinase induce apoptotic death of SH-SY5Y cells. Toxicol Lett 211:18–28
Horan MP, Pichaud N, Ballard JW (2012) Review: quantifying mitochondrial dysfunction in complex diseases of aging. J Gerontol A Biol Sci Med Sci 67:1022–1035
Karbowski M, Neutzner A (2012) Neurodegeneration as a consequence of failed mitochondrial maintenance. Acta Neuropathol 123:157–171
Nunnari J, Suomalainen A (2012) Mitochondria: in sickness and in health. Cell 148:1145–1159
Gottlieb RA, Carreira RS (2010) Autophagy in health and disease. 5. Mitophagy as a way of life. Am J Physiol Cell Physiol 299:C203–C210
Jin SM, Lazarou M, Wang C, Kane LA, Narendra DP, Youle RJ (2010) Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J Cell Biol 191:933–942
Jin SM, Youle RJ (2012) PINK1- and Parkin-mediated mitophagy at a glance. J Cell Sci 125:795–799
Lee JE, Park JH, Shin IC, Koh HC (2012) Reactive oxygen species regulated mitochondria-mediated apoptosis in PC12 cells exposed to chlorpyrifos. Toxicol Appl Pharmacol 263:148–162
Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z (2007) Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 26:1749–1760
Hamanaka RB, Chandel NS (2010) Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes. Trends Biochem Sci 35:505–513
Scherz-Shouval R, Elazar Z (2011) Regulation of autophagy by ROS: physiology and pathology. Trends Biochem Sci 36:30–38
Donati A, Cavallini G, Paradiso C, Vittorini S, Pollera M, Gori Z, Bergamini E (2001) Age-related changes in the autophagic proteolysis of rat isolated liver cells: effects of antiaging dietary restrictions. J Gerontol A Biol Sci Med Sci 56:B375–B383
Underwood BR, Imarisio S, Fleming A, Rose C, Krishna G, Heard P, Quick M, Korolchuk VI et al (2010) Antioxidants can inhibit basal autophagy and enhance neurodegeneration in models of polyglutamine disease. Hum Mol Genet 19:3413–3429
Thyagarajan A, Jedinak A, Nguyen H, Terry C, Baldridge LA, Jiang J, Sliva D (2010) Triterpenes from Ganoderma Lucidum induce autophagy in colon cancer through the inhibition of p38 mitogen-activated kinase (p38 MAPK). Nutr Cancer 62:630–640
Colosetti P, Puissant A, Robert G, Luciano F, Jacquel A, Gounon P, Cassuto JP, Auberger P (2009) Autophagy is an important event for megakaryocytic differentiation of the chronic myelogenous leukemia K562 cell line. Autophagy 5:1092–1098
Menon MB, Kotlyarov A, Gaestel M (2011) SB202190-induced cell type-specific vacuole formation and defective autophagy do not depend on p38 MAP kinase inhibition. PLoS ONE 6, e23054
Chaanine AH, Jeong D, Liang L, Chemaly ER, Fish K, Gordon RE, Hajjar RJ (2012) JNK modulates FOXO3a for the expression of the mitochondrial death and mitophagy marker BNIP3 in pathological hypertrophy and in heart failure. Cell Death Dis 3:265
Wei Y, Pattingre S, Sinha S, Bassik M, Levine B (2008) JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell 30:678–88
Sivaprasad U, Basu A (2008) Inhibition of ERK attenuates autophagy and potentiates tumour necrosis factor-alpha-induced cell death in MCF-7 cells. J Cell Mol Med 12:1265–71
Ki YW, Park JH, Lee JE, Shin IC, Koh HC (2013) JNK and p38 MAPK regulate oxidative stress and the inflammatory response in chlorpyrifos-induced apoptosis. Toxicol Lett 218:235–245
Um JW, Stichel-Gunkel C, Lübbert H, Lee G, Chung KC (2009) Molecular interaction between parkin and PINK1 in mammalian neuronal cells. Mol Cell Neurosci 40:421–432
Kondapalli C, Kazlauskaite A, Zhang N, Woodroof HI, Campbell DG, Gourlay R, Burchell L, Walden H et al (2012) PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65. Open Biol 2:120080
Allen GF, Toth R, James J, Ganley IG (2013) Loss of iron triggers PINK1/Parkin-independent mitophagy. EMBO Rep 14:1127–1135
Ashrafi G, Schlehe JS, LaVoie MJ, Schwarz TL (2014) Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin. J Cell Biol 206:655–670
Acknowledgments
This work was supported by the Korea Science and Engineering Foundation (NRF-2008-0062287) through the Medical Research Center at Hanyang University College of Medicine, Republic of Korea, and by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2010-0024012, NRF-2015R1D1A1A01059531).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of Interest
The authors have no conflicts of interest to declare.
Rights and permissions
About this article
Cite this article
Park, J.H., Ko, J., Park, Y.S. et al. Clearance of Damaged Mitochondria Through PINK1 Stabilization by JNK and ERK MAPK Signaling in Chlorpyrifos-Treated Neuroblastoma Cells. Mol Neurobiol 54, 1844–1857 (2017). https://doi.org/10.1007/s12035-016-9753-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-016-9753-1