Gemcitabine induces Parkin-independent mitophagy through mitochondrial-resident E3 ligase MUL1-mediated stabilization of PINK1.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
30 01 2020
30 01 2020
Historique:
received:
22
10
2019
accepted:
14
01
2020
entrez:
1
2
2020
pubmed:
1
2
2020
medline:
18
11
2020
Statut:
epublish
Résumé
Mitophagy plays an important role in the maintenance of mitochondrial homeostasis. PTEN-induced kinase (PINK1), a key regulator of mitophagy, is degraded constitutively under steady-state conditions. During mitophagy, it becomes stabilized in the outer mitochondrial membrane, particularly under mitochondrial stress conditions, such as in treatment with uncouplers, generation of excessive mitochondrial reactive oxygen species, and formation of protein aggregates in mitochondria. Stabilized PINK1 recruits and activates E3 ligases, such as Parkin and mitochondrial ubiquitin ligase (MUL1), to ubiquitinate mitochondrial proteins and induce ubiquitin-mediated mitophagy. Here, we found that the anticancer drug gemcitabine induces the stabilization of PINK1 and subsequent mitophagy, even in the absence of Parkin. We also found that gemcitabine-induced stabilization of PINK1 was not accompanied by mitochondrial depolarization. Interestingly, the stabilization of PINK1 was mediated by MUL1. These results suggest that gemcitabine induces mitophagy through MUL1-mediated stabilization of PINK1 on the mitochondrial membrane independently of mitochondrial depolarization.
Identifiants
pubmed: 32001742
doi: 10.1038/s41598-020-58315-w
pii: 10.1038/s41598-020-58315-w
pmc: PMC6992789
doi:
Substances chimiques
Antimetabolites, Antineoplastic
0
Deoxycytidine
0W860991D6
MUL1 protein, human
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
parkin protein
EC 2.3.2.27
Protein Kinases
EC 2.7.-
PTEN-induced putative kinase
EC 2.7.11.1
Gemcitabine
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1465Références
Mizushima, N., Yoshimori, T. & Ohsumi, Y. The role of Atg proteins in autophagosome formation. Annu. Rev. Cell Dev. Biol. 27, 107–132, https://doi.org/10.1146/annurev-cellbio-092910-154005 (2011).
doi: 10.1146/annurev-cellbio-092910-154005
pubmed: 21801009
Nakatogawa, H., Suzuki, K., Kamada, Y. & Ohsumi, Y. Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat. Rev. Mol. Cell Biol. 10, 458–467, https://doi.org/10.1038/nrm2708 (2009).
doi: 10.1038/nrm2708
pubmed: 19491929
Farre, J. C. & Subramani, S. Mechanistic insights into selective autophagy pathways: lessons from yeast. Nat. Rev. Mol. Cell Biol. 17, 537–552, https://doi.org/10.1038/nrm.2016.74 (2016).
doi: 10.1038/nrm.2016.74
pubmed: 27381245
pmcid: 5549613
Gatica, D., Lahiri, V. & Klionsky, D. J. Cargo recognition and degradation by selective autophagy. Nat. Cell Biol. 20, 233–242, https://doi.org/10.1038/s41556-018-0037-z (2018).
doi: 10.1038/s41556-018-0037-z
pubmed: 29476151
pmcid: 6028034
Morishita, H. & Mizushima, N. Diverse Cellular Roles of Autophagy. Annu. Rev. Cell Dev. Biol. https://doi.org/10.1146/annurev-cellbio-100818-125300 (2019).
doi: 10.1146/annurev-cellbio-100818-125300
pubmed: 31283377
Lemasters, J. J. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res. 8, 3–5, https://doi.org/10.1089/rej.2005.8.3 (2005).
doi: 10.1089/rej.2005.8.3
pubmed: 15798367
Hamacher-Brady, A. & Brady, N. R. Mitophagy programs: mechanisms and physiological implications of mitochondrial targeting by autophagy. Cell Mol. Life Sci. 73, 775–795, https://doi.org/10.1007/s00018-015-2087-8 (2016).
doi: 10.1007/s00018-015-2087-8
pubmed: 26611876
Khaminets, A., Behl, C. & Dikic, I. Ubiquitin-Dependent And Independent Signals In Selective Autophagy. Trends Cell Biol. 26, 6–16, https://doi.org/10.1016/j.tcb.2015.08.010 (2016).
doi: 10.1016/j.tcb.2015.08.010
pubmed: 26437584
Lazarou, M. et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nat. 524, 309–314, https://doi.org/10.1038/nature14893 (2015).
doi: 10.1038/nature14893
Koyano, F. et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nat. 510, 162–166, https://doi.org/10.1038/nature13392 (2014).
doi: 10.1038/nature13392
Matsuda, N. et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J. Cell Biol. 189, 211–221, https://doi.org/10.1083/jcb.200910140 (2010).
doi: 10.1083/jcb.200910140
pubmed: 20404107
pmcid: 2856912
Narendra, D., Tanaka, A., Suen, D. F. & Youle, R. J. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 183, 795–803, https://doi.org/10.1083/jcb.200809125 (2008).
doi: 10.1083/jcb.200809125
pubmed: 19029340
pmcid: 2592826
Okatsu, K., Kimura, M., Oka, T., Tanaka, K. & Matsuda, N. Unconventional PINK1 localization to the outer membrane of depolarized mitochondria drives Parkin recruitment. J. Cell Sci. 128, 964–978, https://doi.org/10.1242/jcs.161000 (2015).
doi: 10.1242/jcs.161000
pubmed: 25609704
pmcid: 4342580
Sekine, S. & Youle, R. J. PINK1 import regulation; a fine system to convey mitochondrial stress to the cytosol. BMC Biol. 16, 2, https://doi.org/10.1186/s12915-017-0470-7 (2018).
doi: 10.1186/s12915-017-0470-7
pubmed: 29325568
pmcid: 5795276
Narendra, D. P. et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 8, e1000298, https://doi.org/10.1371/journal.pbio.1000298 (2010).
doi: 10.1371/journal.pbio.1000298
pubmed: 20126261
pmcid: 2811155
Ashrafi, G., Schlehe, J. S., LaVoie, M. J. & Schwarz, T. L. Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin. J. Cell Biol. 206, 655–670, https://doi.org/10.1083/jcb.201401070 (2014).
doi: 10.1083/jcb.201401070
pubmed: 25154397
pmcid: 4151150
Burman, J. L. et al. Mitochondrial fission facilitates the selective mitophagy of protein aggregates. J. Cell Biol. 216, 3231–3247, https://doi.org/10.1083/jcb.201612106 (2017).
doi: 10.1083/jcb.201612106
pubmed: 28893839
pmcid: 5626535
Palikaras, K., Lionaki, E. & Tavernarakis, N. Mechanisms of mitophagy in cellular homeostasis, physiology and pathology. Nat. Cell Biol. 20, 1013–1022, https://doi.org/10.1038/s41556-018-0176-2 (2018).
doi: 10.1038/s41556-018-0176-2
pubmed: 30154567
Katayama, H., Kogure, T., Mizushima, N., Yoshimori, T. & Miyawaki, A. A sensitive and quantitative technique for detecting autophagic events based on lysosomal delivery. Chem. Biol. 18, 1042–1052, https://doi.org/10.1016/j.chembiol.2011.05.013 (2011).
doi: 10.1016/j.chembiol.2011.05.013
pubmed: 21867919
pmcid: 21867919
Yamashita, S. I. et al. Mitochondrial division occurs concurrently with autophagosome formation but independently of Drp1 during mitophagy. J. Cell Biol. 215, 649–665, https://doi.org/10.1083/jcb.201605093 (2016).
doi: 10.1083/jcb.201605093
pubmed: 27903607
pmcid: 5147001
Yamashita, S. I. & Kanki, T. Detection of Iron Depletion- and Hypoxia-Induced Mitophagy in Mammalian Cells. Methods Mol. Biol. 1782, 315–324, https://doi.org/10.1007/978-1-4939-7831-1_18 (2018).
doi: 10.1007/978-1-4939-7831-1_18
pubmed: 29851008
Denison, S. R. et al. Alterations in the common fragile site gene Parkin in ovarian and other cancers. Oncogene 22, 8370–8378, https://doi.org/10.1038/sj.onc.1207072 (2003).
doi: 10.1038/sj.onc.1207072
pubmed: 14614460
Park, S. J. et al. Mitochondrial fragmentation caused by phenanthroline promotes mitophagy. FEBS Lett. 586, 4303–4310, https://doi.org/10.1016/j.febslet.2012.10.035 (2012).
doi: 10.1016/j.febslet.2012.10.035
pubmed: 23123158
Okatsu, K. et al. PINK1 autophosphorylation upon membrane potential dissipation is essential for Parkin recruitment to damaged mitochondria. Nat. Commun. 3, 1016, https://doi.org/10.1038/ncomms2016 (2012).
doi: 10.1038/ncomms2016
pubmed: 22910362
pmcid: 3432468
Beilina, A. et al. Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability. Proc. Natl Acad. Sci. USA 102, 5703–5708, https://doi.org/10.1073/pnas.0500617102 (2005).
doi: 10.1073/pnas.0500617102
pubmed: 15824318
Rojansky, R., Cha, M. Y. & Chan, D. C. Elimination of paternal mitochondria in mouse embryos occurs through autophagic degradation dependent on PARKIN and MUL1. Elife 5, https://doi.org/10.7554/eLife.17896 (2016).
Yun, J. et al. MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin. Elife 3, e01958, https://doi.org/10.7554/eLife.01958 (2014).
doi: 10.7554/eLife.01958
pubmed: 24898855
pmcid: 4044952
Braschi, E., Zunino, R. & McBride, H. M. MAPL is a new mitochondrial SUMO E3 ligase that regulates mitochondrial fission. EMBO Rep. 10, 748–754, https://doi.org/10.1038/embor.2009.86 (2009).
doi: 10.1038/embor.2009.86
pubmed: 19407830
pmcid: 2727426
Harder, Z., Zunino, R. & McBride, H. Sumo1 conjugates mitochondrial substrates and participates in mitochondrial fission. Curr. Biol. 14, 340–345, https://doi.org/10.1016/j.cub.2004.02.004 (2004).
doi: 10.1016/j.cub.2004.02.004
pubmed: 14972687
Puri, R., Cheng, X. T., Lin, M. Y., Huang, N. & Sheng, Z. H. Mul1 restrains Parkin-mediated mitophagy in mature neurons by maintaining ER-mitochondrial contacts. Nat. Commun. 10, 3645, https://doi.org/10.1038/s41467-019-11636-5 (2019).
doi: 10.1038/s41467-019-11636-5
pubmed: 31409786
pmcid: 6692330
Wasiak, S., Zunino, R. & McBride, H. M. Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apoptotic cell death. J. Cell Biol. 177, 439–450, https://doi.org/10.1083/jcb.200610042 (2007).
doi: 10.1083/jcb.200610042
pubmed: 17470634
pmcid: 2064824
Zunino, R., Schauss, A., Rippstein, P., Andrade-Navarro, M. & McBride, H. M. The SUMO protease SENP5 is required to maintain mitochondrial morphology and function. J. Cell Sci. 120, 1178–1188, https://doi.org/10.1242/jcs.03418 (2007).
doi: 10.1242/jcs.03418
pubmed: 17341580
Lazarou, M., Jin, S. M., Kane, L. A. & Youle, R. J. Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin. Dev. Cell 22, 320–333, https://doi.org/10.1016/j.devcel.2011.12.014 (2012).
doi: 10.1016/j.devcel.2011.12.014
pubmed: 22280891
pmcid: 3288275
Okatsu, K. et al. A dimeric PINK1-containing complex on depolarized mitochondria stimulates Parkin recruitment. J. Biol. Chem. 288, 36372–36384, https://doi.org/10.1074/jbc.M113.509653 (2013).
doi: 10.1074/jbc.M113.509653
pubmed: 24189060
pmcid: 3868751
Szargel, R. et al. The PINK1, synphilin-1 and SIAH-1 complex constitutes a novel mitophagy pathway. Hum. Mol. Genet. 25, 3476–3490, https://doi.org/10.1093/hmg/ddw189 (2016).
doi: 10.1093/hmg/ddw189
pubmed: 27334109
Villa, E. et al. Parkin-Independent Mitophagy Controls Chemotherapeutic Response in Cancer Cells. Cell Rep. 20, 2846–2859, https://doi.org/10.1016/j.celrep.2017.08.087 (2017).
doi: 10.1016/j.celrep.2017.08.087
pubmed: 28930681