Activation of Mitochondrial Protease OMA1 by Bax and Bak Promotes Cytochrome C Release During Apoptosis

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2014 Oct 3

PMID 25275009

Citations 104

Authors

Xian Jiang

Hui Jiang

Zhirong Shen

Xiaodong Wang

Affiliations

Soon will be listed here.

Abstract

Intrinsic apoptotic stimuli initiate mammalian cells' apoptotic program by first activating the proteins that have only Bcl-2 homology domain 3 (BH3), such as Bcl-2 interacting mediator of cell death (Bim) and truncated BH3 interacting death domain agonist (tBid), which in turn trigger conformational changes in BCL2-associated X (Bax) and BCL2-antagonist/killer (Bak) proteins that enable oligomer formation on the mitochondria, causing cytochrome c and other apoptogenic proteins in the intermembrane space to leak out. Leaked cytochrome c then initiates apoptotic caspase activation through a well-defined biochemical pathway. However, how oligomerized Bax and Bak cause cytochrome c release from mitochondria remains unknown. We report here the establishment of cell lines in which Bim or tBid can be inducibly expressed to initiate apoptosis in a controlled, quantitative manner. We used these cell lines to examine apoptotic events after Bax and Bak oligomerization but before cytochrome c release. The mitochondrial metalloprotease OMA1 was activated in this system in a Bax- and Bak-dependent fashion. Activated OMA1 cleaved the dynamin-like GTPase, optical nerve atrophy 1, an event that is critical for remodeling of mitochondrial cristae. Knockdown or knockout of OMA1 in these cells attenuated cytochrome c release. Thus it is clear that oligomerized Bax and Bak trigger apoptosis by causing both the permeabilization of the mitochondrial outer membrane and activation OMA1.

Citing Articles

The neuroimmune nexus: unraveling the role of the mtDNA-cGAS-STING signal pathway in Alzheimer's disease.

Quan S, Fu X, Cai H, Ren Z, Xu Y, Jia L Mol Neurodegener. 2025; 20(1):25.

PMID: 40038765 PMC: 11877805. DOI: 10.1186/s13024-025-00815-2.

Engineered bio-functional material-based nerve guide conduits for optic nerve regeneration: a view from the cellular perspective, challenges and the future outlook.

Obeng E, Shen B, Wang W, Xie Z, Zhang W, Li Z Regen Biomater. 2025; 12:rbae133.

PMID: 39776856 PMC: 11703557. DOI: 10.1093/rb/rbae133.

Inhibition of mitochondrial OMA1 ameliorates osteosarcoma tumorigenesis.

Chen L, Chen D, Pan Y, Mo Y, Lai B, Chen H Cell Death Dis. 2024; 15(11):786.

PMID: 39487118 PMC: 11530700. DOI: 10.1038/s41419-024-07127-1.

Dynamic death decisions: How mitochondrial dynamics shape cellular commitment to apoptosis and ferroptosis.

Khatun J, Gelles J, Chipuk J Dev Cell. 2024; 59(19):2549-2565.

PMID: 39378840 PMC: 11469553. DOI: 10.1016/j.devcel.2024.09.004.

Mitochondrial membrane potential and oxidative stress interact to regulate Oma1-dependent processing of Opa1 and mitochondrial dynamics.

Fogo G, Raghunayakula S, Emaus K, Torres Torres F, Wider J, Sanderson T FASEB J. 2024; 38(18):e70066.

PMID: 39312414 PMC: 11542587. DOI: 10.1096/fj.202400313R.

References

Quiros P, Ramsay A, Sala D, Fernandez-Vizarra E, Rodriguez F, Peinado J . Loss of mitochondrial protease OMA1 alters processing of the GTPase OPA1 and causes obesity and defective thermogenesis in mice. EMBO J. 2012; 31(9):2117-33. PMC: 3343468. DOI: 10.1038/emboj.2012.70. View

Head B, Griparic L, Amiri M, Gandre-Babbe S, van der Bliek A . Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells. J Cell Biol. 2009; 187(7):959-66. PMC: 2806274. DOI: 10.1083/jcb.200906083. View

Li P, Nijhawan D, Budihardjo I, Srinivasula S, Ahmad M, Alnemri E . Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997; 91(4):479-89. DOI: 10.1016/s0092-8674(00)80434-1. View

Eskes R, Desagher S, Antonsson B, Martinou J . Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Mol Cell Biol. 2000; 20(3):929-35. PMC: 85210. DOI: 10.1128/MCB.20.3.929-935.2000. View

Dejean L, Martinez-Caballero S, Guo L, Hughes C, Teijido O, Ducret T . Oligomeric Bax is a component of the putative cytochrome c release channel MAC, mitochondrial apoptosis-induced channel. Mol Biol Cell. 2005; 16(5):2424-32. PMC: 1087246. DOI: 10.1091/mbc.e04-12-1111. View

Stiburek L, Cesnekova J, Kostkova O, Fornuskova D, Vinsova K, Wenchich L . YME1L controls the accumulation of respiratory chain subunits and is required for apoptotic resistance, cristae morphogenesis, and cell proliferation. Mol Biol Cell. 2012; 23(6):1010-23. PMC: 3302729. DOI: 10.1091/mbc.E11-08-0674. View

Cipolat S, Rudka T, Hartmann D, Costa V, Serneels L, Craessaerts K . Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling. Cell. 2006; 126(1):163-75. DOI: 10.1016/j.cell.2006.06.021. View

Kuwana T, Mackey M, Perkins G, Ellisman M, Latterich M, Schneiter R . Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell. 2002; 111(3):331-42. DOI: 10.1016/s0092-8674(02)01036-x. View

Yamaguchi R, Lartigue L, Perkins G, Scott R, Dixit A, Kushnareva Y . Opa1-mediated cristae opening is Bax/Bak and BH3 dependent, required for apoptosis, and independent of Bak oligomerization. Mol Cell. 2008; 31(4):557-569. PMC: 2636708. DOI: 10.1016/j.molcel.2008.07.010. View

10.

Nechushtan A, Smith C, Lamensdorf I, Yoon S, Youle R . Bax and Bak coalesce into novel mitochondria-associated clusters during apoptosis. J Cell Biol. 2001; 153(6):1265-76. PMC: 2192024. DOI: 10.1083/jcb.153.6.1265. View

11.

Ehses S, Raschke I, Mancuso G, Bernacchia A, Geimer S, Tondera D . Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1. J Cell Biol. 2009; 187(7):1023-36. PMC: 2806285. DOI: 10.1083/jcb.200906084. View

12.

Frezza C, Cipolat S, Martins de Brito O, Micaroni M, Beznoussenko G, Rudka T . OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell. 2006; 126(1):177-89. DOI: 10.1016/j.cell.2006.06.025. View

13.

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

14.

Ren D, Tu H, Kim H, Wang G, Bean G, Takeuchi O . BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program. Science. 2010; 330(6009):1390-3. PMC: 3163443. DOI: 10.1126/science.1190217. View

15.

Kluck R, Bossy-Wetzel E, Green D, Newmeyer D . The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science. 1997; 275(5303):1132-6. DOI: 10.1126/science.275.5303.1132. View

16.

Antonsson B, Montessuit S, Sanchez B, Martinou J . Bax is present as a high molecular weight oligomer/complex in the mitochondrial membrane of apoptotic cells. J Biol Chem. 2001; 276(15):11615-23. DOI: 10.1074/jbc.M010810200. View

17.

Annis M, Soucie E, Dlugosz P, Cruz-Aguado J, Penn L, Leber B . Bax forms multispanning monomers that oligomerize to permeabilize membranes during apoptosis. EMBO J. 2005; 24(12):2096-103. PMC: 1150878. DOI: 10.1038/sj.emboj.7600675. 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.

Song Z, Chen H, Fiket M, Alexander C, Chan D . OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J Cell Biol. 2007; 178(5):749-55. PMC: 2064540. DOI: 10.1083/jcb.200704110. View

20.

Lovell J, Billen L, Bindner S, Shamas-Din A, Fradin C, Leber B . Membrane binding by tBid initiates an ordered series of events culminating in membrane permeabilization by Bax. Cell. 2008; 135(6):1074-84. DOI: 10.1016/j.cell.2008.11.010. View