Stress-induced OMA1 Activation and Autocatalytic Turnover Regulate OPA1-dependent Mitochondrial Dynamics

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2014 Feb 20

PMID 24550258

Citations 166

Authors

Michael J Baker

Philipp A Lampe

Diana Stojanovski

Anne Korwitz

Ruchika Anand

Takashi Tatsuta

Thomas Langer

Affiliations

Soon will be listed here.

Abstract

The dynamic network of mitochondria fragments under stress allowing the segregation of damaged mitochondria and, in case of persistent damage, their selective removal by mitophagy. Mitochondrial fragmentation upon depolarisation of mitochondria is brought about by the degradation of central components of the mitochondrial fusion machinery. The OMA1 peptidase mediates the degradation of long isoforms of the dynamin-like GTPase OPA1 in the inner membrane. Here, we demonstrate that OMA1-mediated degradation of OPA1 is a general cellular stress response. OMA1 is constitutively active but displays strongly enhanced activity in response to various stress insults. We identify an amino terminal stress-sensor domain of OMA1, which is only present in homologues of higher eukaryotes and which modulates OMA1 proteolysis and activation. OMA1 activation is associated with its autocatalyic degradation, which initiates from both termini of OMA1 and results in complete OMA1 turnover. Autocatalytic proteolysis of OMA1 ensures the reversibility of the response and allows OPA1-mediated mitochondrial fusion to resume upon alleviation of stress. This differentiated stress response maintains the functional integrity of mitochondria and contributes to cell survival.

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References

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

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

Kaser M, Kambacheld M, Kisters-Woike B, Langer T . Oma1, a novel membrane-bound metallopeptidase in mitochondria with activities overlapping with the m-AAA protease. J Biol Chem. 2003; 278(47):46414-23. DOI: 10.1074/jbc.M305584200. View

Tondera D, Grandemange S, Jourdain A, Karbowski M, Mattenberger Y, Herzig S . SLP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J. 2009; 28(11):1589-600. PMC: 2693158. DOI: 10.1038/emboj.2009.89. View

Cipolat S, Martins de Brito O, Dal Zilio B, Scorrano L . OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci U S A. 2004; 101(45):15927-32. PMC: 528769. DOI: 10.1073/pnas.0407043101. View

Khalimonchuk O, Jeong M, Watts T, Ferris E, Winge D . Selective Oma1 protease-mediated proteolysis of Cox1 subunit of cytochrome oxidase in assembly mutants. J Biol Chem. 2012; 287(10):7289-300. PMC: 3293553. DOI: 10.1074/jbc.M111.313148. View

Nunnari J, Suomalainen A . Mitochondria: in sickness and in health. Cell. 2012; 148(6):1145-59. PMC: 5381524. DOI: 10.1016/j.cell.2012.02.035. View

Vives-Bauza C, Zhou C, Huang Y, Cui M, de Vries R, Kim J . PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci U S A. 2009; 107(1):378-83. PMC: 2806779. DOI: 10.1073/pnas.0911187107. View

10.

Rambold A, Kostelecky B, Elia N, Lippincott-Schwartz J . Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci U S A. 2011; 108(25):10190-5. PMC: 3121813. DOI: 10.1073/pnas.1107402108. View

11.

Twig G, Elorza A, Molina A, Mohamed H, Wikstrom J, Walzer G . Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 2008; 27(2):433-46. PMC: 2234339. DOI: 10.1038/sj.emboj.7601963. View

12.

Youle R, Narendra D . Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2010; 12(1):9-14. PMC: 4780047. DOI: 10.1038/nrm3028. View

13.

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

14.

Griparic L, Kanazawa T, van der Bliek A . Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage. J Cell Biol. 2007; 178(5):757-64. PMC: 2064541. DOI: 10.1083/jcb.200704112. View

15.

Olichon A, Baricault L, Gas N, Guillou E, Valette A, Belenguer P . Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem. 2003; 278(10):7743-6. DOI: 10.1074/jbc.C200677200. View

16.

Merkwirth C, Dargazanli S, Tatsuta T, Geimer S, Lower B, Wunderlich F . Prohibitins control cell proliferation and apoptosis by regulating OPA1-dependent cristae morphogenesis in mitochondria. Genes Dev. 2008; 22(4):476-88. PMC: 2238669. DOI: 10.1101/gad.460708. View

17.

Chan D . Fusion and fission: interlinked processes critical for mitochondrial health. Annu Rev Genet. 2012; 46:265-87. DOI: 10.1146/annurev-genet-110410-132529. View

18.

Lopez-Pelegrin M, Cerda-Costa N, Martinez-Jimenez F, Cintas-Pedrola A, Canals A, Peinado J . A novel family of soluble minimal scaffolds provides structural insight into the catalytic domains of integral membrane metallopeptidases. J Biol Chem. 2013; 288(29):21279-21294. PMC: 3774397. DOI: 10.1074/jbc.M113.476580. View

19.

Gomes L, Benedetto G, Scorrano L . During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol. 2011; 13(5):589-98. PMC: 3088644. DOI: 10.1038/ncb2220. View

20.

Cereghetti G, Stangherlin A, Martins de Brito O, Chang C, Blackstone C, Bernardi P . Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc Natl Acad Sci U S A. 2008; 105(41):15803-8. PMC: 2572940. DOI: 10.1073/pnas.0808249105. View