9eii

Structural highlights

Disease

PINK1_HUMAN Young-onset Parkinson disease. The disease is caused by variants affecting the gene represented in this entry.

Function

PINK1_HUMAN Serine/threonine-protein kinase which acts as a sensor of mitochondrial damage and protects against mitochondrial dysfunction during cellular stress. It phosphorylates mitochondrial proteins to coordinate mitochondrial quality control mechanisms that remove and replace dysfunctional mitochondrial components (PubMed:14607334, PubMed:15087508, PubMed:18443288, PubMed:18957282, PubMed:19229105, PubMed:19966284, PubMed:20404107, PubMed:20547144, PubMed:20798600, PubMed:22396657, PubMed:23620051, PubMed:23754282, PubMed:23933751, PubMed:24660806, PubMed:24751536, PubMed:24784582, PubMed:24896179, PubMed:24898855, PubMed:25527291, PubMed:32484300). Depending on the severity of mitochondrial damage, activity ranges from preventing apoptosis and stimulating mitochondrial biogenesis to eliminating severely damaged mitochondria via PINK1-PRKN-dependent mitophagy (PubMed:14607334, PubMed:15087508, PubMed:18443288, PubMed:19966284, PubMed:20404107, PubMed:20798600, PubMed:22396657, PubMed:23620051, PubMed:23933751, PubMed:24898855, PubMed:32047033, PubMed:32484300). When cellular stress results in irreversible mitochondrial damage, PINK1 accumulates at the outer mitochondrial membrane (OMM) where it phosphorylates pre-existing polyubiquitin chains at 'Ser-65', recruits PRKN from the cytosol to the OMM and activates PRKN by phosphorylation at 'Ser-65'; activated PRKN then ubiquinates VDAC1 and other OMM proteins to initiate mitophagy (PubMed:14607334, PubMed:15087508, PubMed:19966284, PubMed:20404107, PubMed:20798600, PubMed:23754282, PubMed:23933751, PubMed:24660806, PubMed:24751536, PubMed:24784582, PubMed:25474007, PubMed:25527291, PubMed:32047033). The PINK1-PRKN pathway also promotes fission of damaged mitochondria through phosphorylation and PRKN-dependent degradation of mitochondrial proteins involved in fission such as MFN2 (PubMed:18443288, PubMed:23620051, PubMed:24898855). This prevents the refusion of unhealthy mitochondria with the mitochondrial network or initiates mitochondrial fragmentation facilitating their later engulfment by autophagosomes (PubMed:18443288, PubMed:23620051). Also promotes mitochondrial fission independently of PRKN and ATG7-mediated mitophagy, via the phosphorylation and activation of DNM1L (PubMed:18443288, PubMed:32484300). Regulates motility of damaged mitochondria by promoting the ubiquitination and subsequent degradation of MIRO1 and MIRO2; in motor neurons, this likely inhibits mitochondrial intracellular anterograde transport along the axons which probably increases the chance of the mitochondria undergoing mitophagy in the soma (PubMed:22396657). Required for ubiquinone reduction by mitochondrial complex I by mediating phosphorylation of complex I subunit NDUFA10 (By similarity). Phosphorylates LETM1, positively regulating its mitochondrial calcium transport activity (PubMed:29123128).[UniProtKB:Q99MQ3]^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23]}

References

1. ↑ Nakajima A, Kataoka K, Hong M, Sakaguchi M, Huh NH. BRPK, a novel protein kinase showing increased expression in mouse cancer cell lines with higher metastatic potential. Cancer Lett. 2003 Nov 25;201(2):195-201. PMID:14607334 doi:10.1016/s0304-3835(03)00443-9
2. ↑ Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, González-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science. 2004 May 21;304(5674):1158-60. PMID:15087508 doi:10.1126/science.1096284
3. ↑ Yang Y, Ouyang Y, Yang L, Beal MF, McQuibban A, Vogel H, Lu B. Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. Proc Natl Acad Sci U S A. 2008 May 13;105(19):7070-5. PMID:18443288 doi:10.1073/pnas.0711845105
4. ↑ Kim Y, Park J, Kim S, Song S, Kwon SK, Lee SH, Kitada T, Kim JM, Chung J. PINK1 controls mitochondrial localization of Parkin through direct phosphorylation. Biochem Biophys Res Commun. 2008 Dec 19;377(3):975-80. PMID:18957282 doi:10.1016/j.bbrc.2008.10.104
5. ↑ Xiong H, Wang D, Chen L, Choo YS, Ma H, Tang C, Xia K, Jiang W, Ronai Z, Zhuang X, Zhang Z. Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation. J Clin Invest. 2009 Mar;119(3):650-60. doi: 10.1172/JCI37617. Epub 2009 Feb 23. PMID:19229105 doi:http://dx.doi.org/10.1172/JCI37617
6. ↑ 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. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):378-83. doi: 10.1073/pnas.0911187107., Epub 2009 Dec 4. PMID:19966284 doi:10.1073/pnas.0911187107
7. ↑ Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier CA, Sou YS, Saiki S, Kawajiri S, Sato F, Kimura M, Komatsu M, Hattori N, Tanaka K. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol. 2010 Apr 19;189(2):211-21. doi: 10.1083/jcb.200910140. PMID:20404107 doi:10.1083/jcb.200910140
8. ↑ Yuan XL, Guo JF, Shi ZH, Xiao ZQ, Yan XX, Zhao BL, Tang BS. R492X mutation in PTEN-induced putative kinase 1 induced cellular mitochondrial dysfunction and oxidative stress. Brain Res. 2010 Sep 10;1351:229-237. PMID:20547144 doi:10.1016/j.brainres.2010.06.005
9. ↑ Geisler S, Holmström KM, Treis A, Skujat D, Weber SS, Fiesel FC, Kahle PJ, Springer W. The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations. Autophagy. 2010 Oct;6(7):871-8. PMID:20798600 doi:10.4161/auto.6.7.13286
10. ↑ Liu S, Sawada T, Lee S, Yu W, Silverio G, Alapatt P, Millan I, Shen A, Saxton W, Kanao T, Takahashi R, Hattori N, Imai Y, Lu B. Parkinson's disease-associated kinase PINK1 regulates Miro protein level and axonal transport of mitochondria. PLoS Genet. 2012;8(3):e1002537. PMID:22396657 doi:10.1371/journal.pgen.1002537
11. ↑ Chen Y, Dorn GW 2nd. PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science. 2013 Apr 26;340(6131):471-5. doi: 10.1126/science.1231031. PMID:23620051 doi:http://dx.doi.org/10.1126/science.1231031
12. ↑ Iguchi M, Kujuro Y, Okatsu K, Koyano F, Kosako H, Kimura M, Suzuki N, Uchiyama S, Tanaka K, Matsuda N. Parkin-catalyzed ubiquitin-ester transfer is triggered by PINK1-dependent phosphorylation. J Biol Chem. 2013 Jul 26;288(30):22019-32. doi: 10.1074/jbc.M113.467530. Epub, 2013 Jun 10. PMID:23754282 doi:http://dx.doi.org/10.1074/jbc.M113.467530
13. ↑ Burchell VS, Nelson DE, Sanchez-Martinez A, Delgado-Camprubi M, Ivatt RM, Pogson JH, Randle SJ, Wray S, Lewis PA, Houlden H, Abramov AY, Hardy J, Wood NW, Whitworth AJ, Laman H, Plun-Favreau H. The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy. Nat Neurosci. 2013 Sep;16(9):1257-65. doi: 10.1038/nn.3489. Epub 2013 Aug 11. PMID:23933751 doi:http://dx.doi.org/10.1038/nn.3489
14. ↑ Kazlauskaite A, Kondapalli C, Gourlay R, Campbell DG, Ritorto MS, Hofmann K, Alessi DR, Knebel A, Trost M, Muqit MM. Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65. Biochem J. 2014 May 15;460(1):127-39. doi: 10.1042/BJ20140334. PMID:24660806 doi:http://dx.doi.org/10.1042/BJ20140334
15. ↑ Kane LA, Lazarou M, Fogel AI, Li Y, Yamano K, Sarraf SA, Banerjee S, Youle RJ. PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol. 2014 Apr 28;205(2):143-53. doi: 10.1083/jcb.201402104. Epub 2014 Apr, 21. PMID:24751536 doi:http://dx.doi.org/10.1083/jcb.201402104
16. ↑ Koyano F, Okatsu K, Kosako H, Tamura Y, Go E, Kimura M, Kimura Y, Tsuchiya H, Yoshihara H, Hirokawa T, Endo T, Fon EA, Trempe JF, Saeki Y, Tanaka K, Matsuda N. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature. 2014 Jun 5;510(7503):162-6. doi: 10.1038/nature13392. Epub 2014 Jun 4. PMID:24784582 doi:http://dx.doi.org/10.1038/nature13392
17. ↑ Bingol B, Tea JS, Phu L, Reichelt M, Bakalarski CE, Song Q, Foreman O, Kirkpatrick DS, Sheng M. The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature. 2014 Jun 19;510(7505):370-5. doi: 10.1038/nature13418. Epub 2014 Jun 4. PMID:24896179 doi:http://dx.doi.org/10.1038/nature13418
18. ↑ Yun J, Puri R, Yang H, Lizzio MA, Wu C, Sheng ZH, Guo M. MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin. Elife. 2014 Jun 4;3:e01958. doi: 10.7554/eLife.01958. PMID:24898855 doi:http://dx.doi.org/10.7554/eLife.01958
19. ↑ Shiba-Fukushima K, Arano T, Matsumoto G, Inoshita T, Yoshida S, Ishihama Y, Ryu KY, Nukina N, Hattori N, Imai Y. Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes Parkin mitochondrial tethering. PLoS Genet. 2014 Dec 4;10(12):e1004861. doi: 10.1371/journal.pgen.1004861. , eCollection 2014 Dec. PMID:25474007 doi:http://dx.doi.org/10.1371/journal.pgen.1004861
20. ↑ Wauer T, Swatek KN, Wagstaff JL, Gladkova C, Pruneda JN, Michel MA, Gersch M, Johnson CM, Freund SM, Komander D. Ubiquitin Ser65 phosphorylation affects ubiquitin structure, chain assembly and hydrolysis. EMBO J. 2014 Dec 19. pii: e201489847. PMID:25527291 doi:http://dx.doi.org/10.15252/embj.201489847
21. ↑ Huang E, Qu D, Huang T, Rizzi N, Boonying W, Krolak D, Ciana P, Woulfe J, Klein C, Slack RS, Figeys D, Park DS. PINK1-mediated phosphorylation of LETM1 regulates mitochondrial calcium transport and protects neurons against mitochondrial stress. Nat Commun. 2017 Nov 9;8(1):1399. PMID:29123128 doi:10.1038/s41467-017-01435-1
22. ↑ Ham SJ, Lee D, Yoo H, Jun K, Shin H, Chung J. Decision between mitophagy and apoptosis by Parkin via VDAC1 ubiquitination. Proc Natl Acad Sci U S A. 2020 Feb 25;117(8):4281-4291. doi: , 10.1073/pnas.1909814117. Epub 2020 Feb 11. PMID:32047033 doi:http://dx.doi.org/10.1073/pnas.1909814117
23. ↑ Han H, Tan J, Wang R, Wan H, He Y, Yan X, Guo J, Gao Q, Li J, Shang S, Chen F, Tian R, Liu W, Liao L, Tang B, Zhang Z. PINK1 phosphorylates Drp1(S616) to regulate mitophagy-independent mitochondrial dynamics. EMBO Rep. 2020 Aug 5;21(8):e48686. PMID:32484300 doi:10.15252/embr.201948686