MiR-218 Inhibits Mitochondrial Clearance by Targeting PRKN E3 Ubiquitin Ligase

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2020 Jan 18

PMID 31948106

Citations 19

Authors

Anthea Di Rita

Teresa Maiorino

Krenare Bruqi

Floriana Volpicelli

Gian Carlo Bellenchi

Flavie Strappazzon

Affiliations

Soon will be listed here.

Abstract

The selective elimination of dysfunctional mitochondria through mitophagy is crucial for preserving mitochondrial quality and cellular homeostasis. The most described mitophagy pathway is regulated by a positive ubiquitylation feedback loop in which the PINK1 (PTEN induced kinase 1) kinase phosphorylates both ubiquitin and the E3 ubiquitin ligase PRKN (Parkin RBR E3 ubiquitin ligase), also known as PARKIN. This event recruits PRKN to the mitochondria, thus amplifying ubiquitylation signal. Here we report that miR-218 targets PRKN and negatively regulates PINK1/PRKN-mediated mitophagy. Overexpression of miR-218 reduces PRKN mRNA levels, thus also reducing protein content and deregulating the E3 ubiquitin ligase action. In fact, following miR-218 overexpression, mitochondria result less ubiquitylated and the autophagy machinery fails to proceed with correct mitochondrial clearance. Since mitophagy defects are associated with various human diseases, these results qualify miR-218 as a promising therapeutic target for human diseases.

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References

Radogna F, Cerella C, Gaigneaux A, Christov C, Dicato M, Diederich M . Cell type-dependent ROS and mitophagy response leads to apoptosis or necroptosis in neuroblastoma. Oncogene. 2015; 35(29):3839-53. DOI: 10.1038/onc.2015.455. View

Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier C . PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol. 2010; 189(2):211-21. PMC: 2856912. DOI: 10.1083/jcb.200910140. View

Wei Y, Chiang W, Sumpter Jr R, Mishra P, Levine B . Prohibitin 2 Is an Inner Mitochondrial Membrane Mitophagy Receptor. Cell. 2016; 168(1-2):224-238.e10. PMC: 5235968. DOI: 10.1016/j.cell.2016.11.042. View

Cecconi F, Levine B . The role of autophagy in mammalian development: cell makeover rather than cell death. Dev Cell. 2008; 15(3):344-357. PMC: 2688784. DOI: 10.1016/j.devcel.2008.08.012. View

Tsai Y, Fishman P, Thakor N, Oyler G . Parkin facilitates the elimination of expanded polyglutamine proteins and leads to preservation of proteasome function. J Biol Chem. 2003; 278(24):22044-55. DOI: 10.1074/jbc.M212235200. View

Mauthe M, Orhon I, Rocchi C, Zhou X, Luhr M, Hijlkema K . Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy. 2018; 14(8):1435-1455. PMC: 6103682. DOI: 10.1080/15548627.2018.1474314. View

Sandoval H, Thiagarajan P, Dasgupta S, Schumacher A, Prchal J, Chen M . Essential role for Nix in autophagic maturation of erythroid cells. Nature. 2008; 454(7201):232-5. PMC: 2570948. DOI: 10.1038/nature07006. View

Liu J, Zhang C, Zhao Y, Yue X, Wu H, Huang S . Parkin targets HIF-1α for ubiquitination and degradation to inhibit breast tumor progression. Nat Commun. 2017; 8(1):1823. PMC: 5703960. DOI: 10.1038/s41467-017-01947-w. View

Liu K, Yan L, Jiang X, Yu Y, Liu H, Gu T . Acquired inhibition of microRNA-124 protects against spinal cord ischemia-reperfusion injury partially through a mitophagy-dependent pathway. J Thorac Cardiovasc Surg. 2017; 154(5):1498-1508. DOI: 10.1016/j.jtcvs.2017.05.046. View

10.

Indrieri A, Carrella S, Romano A, Spaziano A, Marrocco E, Fernandez-Vizarra E . miR-181a/b downregulation exerts a protective action on mitochondrial disease models. EMBO Mol Med. 2019; 11(5. PMC: 6505685. DOI: 10.15252/emmm.201708734. View

11.

Gottlieb R, Thomas A . Mitophagy and Mitochondrial Quality Control Mechanisms in the Heart. Curr Pathobiol Rep. 2017; 5(2):161-169. PMC: 5656254. DOI: 10.1007/s40139-017-0133-y. View

12.

Jing Z, Han W, Sui X, Xie J, Pan H . Interaction of autophagy with microRNAs and their potential therapeutic implications in human cancers. Cancer Lett. 2014; 356(2 Pt B):332-8. DOI: 10.1016/j.canlet.2014.09.039. View

13.

Kane L, Lazarou M, Fogel A, Li Y, Yamano K, Sarraf S . PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol. 2014; 205(2):143-53. PMC: 4003245. DOI: 10.1083/jcb.201402104. View

14.

Tatsuta T, Langer T . Quality control of mitochondria: protection against neurodegeneration and ageing. EMBO J. 2008; 27(2):306-14. PMC: 2234350. DOI: 10.1038/sj.emboj.7601972. View

15.

Lemasters J . Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res. 2005; 8(1):3-5. DOI: 10.1089/rej.2005.8.3. View

16.

Tay S, Yeo C, Chai C, Chua P, Tan H, Ang A . Parkin enhances the expression of cyclin-dependent kinase 6 and negatively regulates the proliferation of breast cancer cells. J Biol Chem. 2010; 285(38):29231-8. PMC: 2937954. DOI: 10.1074/jbc.M110.108241. View

17.

Koyano F, Okatsu K, Kosako H, Tamura Y, Go E, Kimura M . Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature. 2014; 510(7503):162-6. DOI: 10.1038/nature13392. View

18.

Sugiura A, McLelland G, Fon E, McBride H . A new pathway for mitochondrial quality control: mitochondrial-derived vesicles. EMBO J. 2014; 33(19):2142-56. PMC: 4282503. DOI: 10.15252/embj.201488104. View

19.

Murakawa T, Yamaguchi O, Hashimoto A, Hikoso S, Takeda T, Oka T . Bcl-2-like protein 13 is a mammalian Atg32 homologue that mediates mitophagy and mitochondrial fragmentation. Nat Commun. 2015; 6:7527. PMC: 4501433. DOI: 10.1038/ncomms8527. View

20.

Di Rita A, Peschiaroli A, D Acunzo P, Strobbe D, Hu Z, Gruber J . HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα. Nat Commun. 2018; 9(1):3755. PMC: 6138665. DOI: 10.1038/s41467-018-05722-3. View