Parkin Inhibits BAK and BAX Apoptotic Function by Distinct Mechanisms During Mitophagy

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2018 Dec 22

PMID 30573668

Citations 46

Authors

Jonathan P Bernardini

Jason M Brouwer

Iris Kl Tan

Jarrod J Sandow

Shuai Huang

Che A Stafford

Aleksandra Bankovacki

Christopher D Riffkin

Ahmad Z Wardak

Peter E Czabotar

Michael Lazarou

Grant Dewson

Affiliations

Soon will be listed here.

Abstract

The E3 ubiquitin ligase Parkin is a key effector of the removal of damaged mitochondria by mitophagy. Parkin determines cell fate in response to mitochondrial damage, with its loss promoting early onset Parkinson's disease and potentially also cancer progression. Controlling a cell's apoptotic response is essential to co-ordinate the removal of damaged mitochondria. We report that following mitochondrial damage-induced mitophagy, Parkin directly ubiquitinates the apoptotic effector protein BAK at a conserved lysine in its hydrophobic groove, a region that is crucial for BAK activation by BH3-only proteins and its homo-dimerisation during apoptosis. Ubiquitination inhibited BAK activity by impairing its activation and the formation of lethal BAK oligomers. Parkin also suppresses BAX-mediated apoptosis, but in the absence of BAX ubiquitination suggesting an indirect mechanism. In addition, we find that BAK-dependent mitochondrial outer membrane permeabilisation during apoptosis promotes PINK1-dependent Parkin activation. Hence, we propose that Parkin directly inhibits BAK to suppress errant apoptosis, thereby allowing the effective clearance of damaged mitochondria, but also promotes clearance of apoptotic mitochondria to limit their potential pro-inflammatory effect.

Citing Articles

Important regulatory role of mitophagy in diabetic microvascular complications.

Hu X, Lv J, Zhao Y, Li X, Qi W, Wang X J Transl Med. 2025; 23(1):269.

PMID: 40038741 PMC: 11877814. DOI: 10.1186/s12967-025-06307-7.

Ailanthone blocks mitophagy to promote mtDNA leakage through BAX-BAK1 pores and suppress hepatocellular carcinoma cell proliferation.

Qin Y, Gao Y, Wu D, Liu Q, Su C, Liu G Front Pharmacol. 2024; 15:1509482.

PMID: 39723259 PMC: 11668963. DOI: 10.3389/fphar.2024.1509482.

Oxygen vacancy-engineered cerium oxide mediated by copper-platinum exhibit enhanced SOD/CAT-mimicking activities to regulate the microenvironment for osteoarthritis therapy.

Yang J, Xiao S, Deng J, Li Y, Hu H, Wang J J Nanobiotechnology. 2024; 22(1):491.

PMID: 39155382 PMC: 11330606. DOI: 10.1186/s12951-024-02678-z.

Mitochondrial Dysfunction is a Crucial Immune Checkpoint for Neuroinflammation and Neurodegeneration: mtDAMPs in Focus.

Mishra Y, Kumar A, Kaundal R Mol Neurobiol. 2024; .

PMID: 39115673 DOI: 10.1007/s12035-024-04412-0.

Yang M, Wei X, Yi X, Jiang D Cell Death Dis. 2024; 15(7):505.

PMID: 39013891 PMC: 11252137. DOI: 10.1038/s41419-024-06804-5.

References

Oltersdorf T, Elmore S, Shoemaker A, Armstrong R, Augeri D, Belli B . An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005; 435(7042):677-81. DOI: 10.1038/nature03579. View

Sliter D, Martinez J, Hao L, Chen X, Sun N, Fischer T . Parkin and PINK1 mitigate STING-induced inflammation. Nature. 2018; 561(7722):258-262. PMC: 7362342. DOI: 10.1038/s41586-018-0448-9. View

Petros A, Nettesheim D, Wang Y, Olejniczak E, Meadows R, Mack J . Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies. Protein Sci. 2001; 9(12):2528-34. PMC: 2144516. DOI: 10.1110/ps.9.12.2528. View

Martinez A, Lectez B, Ramirez J, Popp O, Sutherland J, Urbe S . Quantitative proteomic analysis of Parkin substrates in Drosophila neurons. Mol Neurodegener. 2017; 12(1):29. PMC: 5387213. DOI: 10.1186/s13024-017-0170-3. View

McLelland G, Goiran T, Yi W, Dorval G, Chen C, Lauinger N . Mfn2 ubiquitination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy. Elife. 2018; 7. PMC: 5927771. DOI: 10.7554/eLife.32866. View

Chan N, Salazar A, Pham A, Sweredoski M, Kolawa N, Graham R . Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum Mol Genet. 2011; 20(9):1726-37. PMC: 3071670. DOI: 10.1093/hmg/ddr048. View

Lazarou M, Sliter D, Kane L, Sarraf S, Wang C, Burman J . The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature. 2015; 524(7565):309-314. PMC: 5018156. DOI: 10.1038/nature14893. View

Moldoveanu T, Liu Q, Tocilj A, Watson M, Shore G, Gehring K . The X-ray structure of a BAK homodimer reveals an inhibitory zinc binding site. Mol Cell. 2006; 24(5):677-688. DOI: 10.1016/j.molcel.2006.10.014. View

Czabotar P, Westphal D, Dewson G, Ma S, Hockings C, Fairlie W . Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis. Cell. 2013; 152(3):519-31. DOI: 10.1016/j.cell.2012.12.031. View

10.

Zhang Z, Zhu W, Lapolla S, Miao Y, Shao Y, Falcone M . Bax forms an oligomer via separate, yet interdependent, surfaces. J Biol Chem. 2010; 285(23):17614-27. PMC: 2878526. DOI: 10.1074/jbc.M110.113456. View

11.

Yamagata H, Shimizu S, Nishida Y, Watanabe Y, Craigen W, Tsujimoto Y . Requirement of voltage-dependent anion channel 2 for pro-apoptotic activity of Bax. Oncogene. 2009; 28(40):3563-72. DOI: 10.1038/onc.2009.213. View

12.

Kumar A, Aguirre J, Condos T, Martinez-Torres R, Chaugule V, Toth R . Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis. EMBO J. 2015; 34(20):2506-21. PMC: 4609183. DOI: 10.15252/embj.201592337. View

13.

Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno A, Le Toumelin-Braizat G . The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016; 538(7626):477-482. DOI: 10.1038/nature19830. View

14.

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

15.

Tang M, Vranas M, Krahn A, Pundlik S, Trempe J, Fon E . Structure-guided mutagenesis reveals a hierarchical mechanism of Parkin activation. Nat Commun. 2017; 8:14697. PMC: 5347139. DOI: 10.1038/ncomms14697. View

16.

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

17.

McArthur K, Whitehead L, Heddleston J, Li L, Padman B, Oorschot V . BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science. 2018; 359(6378). DOI: 10.1126/science.aao6047. View

18.

Wei M, Zong W, Cheng E, LINDSTEN T, Panoutsakopoulou V, Ross A . Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science. 2001; 292(5517):727-30. PMC: 3049805. DOI: 10.1126/science.1059108. View

19.

Munch C, Harper J . Mitochondrial unfolded protein response controls matrix pre-RNA processing and translation. Nature. 2016; 534(7609):710-3. PMC: 4939261. DOI: 10.1038/nature18302. View

20.

Zhang C, Lee S, Peng Y, Bunker E, Giaime E, Shen J . PINK1 triggers autocatalytic activation of Parkin to specify cell fate decisions. Curr Biol. 2014; 24(16):1854-65. PMC: 4143385. DOI: 10.1016/j.cub.2014.07.014. View