The Soluble Form of Bax Regulates Mitochondrial Fusion Via MFN2 Homotypic Complexes

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2011 Jan 25

PMID 21255726

Citations 130

Authors

Suzanne Hoppins

Frank Edlich

Megan M Cleland

Soojay Banerjee

J Michael McCaffery

Richard J Youle

Jodi Nunnari

Affiliations

Soon will be listed here.

Abstract

In mammals, fusion of the mitochondrial outer membrane is controlled by two DRPs, MFN1 and MFN2, that function in place of a single outer membrane DRP, Fzo1 in yeast. We addressed the significance of two mammalian outer membrane fusion DRPs using an in vitro mammalian mitochondrial fusion assay. We demonstrate that heterotypic MFN1-MFN2 trans complexes possess greater efficacy in fusion as compared to homotypic MFN1 or MFN2 complexes. In addition, we show that the soluble form of the proapoptotic Bcl2 protein, Bax, positively regulates mitochondrial fusion exclusively through homotypic MFN2 trans complexes. Together, these data demonstrate functional and regulatory distinctions between MFN1 and MFN2 and provide insight into their unique physiological roles.

Citing Articles

Apoptotic and proliferative processes in the small intestine of rats with type 2 diabetes mellitus after metformin and propionic acid treatment.

Natrus L, Lisakovska O, Smirnov A, Osadchuk Y, Klys Y Front Pharmacol. 2024; 15:1477793.

PMID: 39478962 PMC: 11521949. DOI: 10.3389/fphar.2024.1477793.

Molecular mechanisms of mitochondrial dynamics.

Tabara L, Segawa M, Prudent J Nat Rev Mol Cell Biol. 2024; 26(2):123-146.

PMID: 39420231 DOI: 10.1038/s41580-024-00785-1.

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.

New Insights into Mitochondria in Health and Diseases.

Li Y, Zhang H, Yu C, Dong X, Yang F, Wang M Int J Mol Sci. 2024; 25(18).

PMID: 39337461 PMC: 11432609. DOI: 10.3390/ijms25189975.

Mitochondria and cell death.

Glover H, Schreiner A, Dewson G, Tait S Nat Cell Biol. 2024; 26(9):1434-1446.

PMID: 38902422 DOI: 10.1038/s41556-024-01429-4.

References

George N, Evans J, Luo X . A three-helix homo-oligomerization domain containing BH3 and BH1 is responsible for the apoptotic activity of Bax. Genes Dev. 2007; 21(15):1937-48. PMC: 1935031. DOI: 10.1101/gad.1553607. View

Detmer S, Chan D . Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations. J Cell Biol. 2007; 176(4):405-14. PMC: 2063976. DOI: 10.1083/jcb.200611080. 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

Chen H, Detmer S, Ewald A, Griffin E, Fraser S, Chan D . Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol. 2003; 160(2):189-200. PMC: 2172648. DOI: 10.1083/jcb.200211046. View

Sugioka R, Shimizu S, Tsujimoto Y . Fzo1, a protein involved in mitochondrial fusion, inhibits apoptosis. J Biol Chem. 2004; 279(50):52726-34. DOI: 10.1074/jbc.M408910200. View

Neuspiel M, Zunino R, Gangaraju S, Rippstein P, McBride H . Activated mitofusin 2 signals mitochondrial fusion, interferes with Bax activation, and reduces susceptibility to radical induced depolarization. J Biol Chem. 2005; 280(26):25060-70. DOI: 10.1074/jbc.M501599200. View

Cartoni R, Martinou J . Role of mitofusin 2 mutations in the physiopathology of Charcot-Marie-Tooth disease type 2A. Exp Neurol. 2009; 218(2):268-73. DOI: 10.1016/j.expneurol.2009.05.003. View

Fang L, Moore X, Gao X, Dart A, Lim Y, Du X . Down-regulation of mitofusin-2 expression in cardiac hypertrophy in vitro and in vivo. Life Sci. 2007; 80(23):2154-2160. DOI: 10.1016/j.lfs.2007.04.003. View

Ishihara N, Eura Y, Mihara K . Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity. J Cell Sci. 2004; 117(Pt 26):6535-46. DOI: 10.1242/jcs.01565. View

10.

Malka F, Guillery O, Cifuentes-Diaz C, Guillou E, Belenguer P, Lombes A . Separate fusion of outer and inner mitochondrial membranes. EMBO Rep. 2005; 6(9):853-9. PMC: 1369163. DOI: 10.1038/sj.embor.7400488. View

11.

Schauss A, Huang H, Choi S, Xu L, Soubeyrand S, Bilodeau P . A novel cell-free mitochondrial fusion assay amenable for high-throughput screenings of fusion modulators. BMC Biol. 2010; 8:100. PMC: 2919466. DOI: 10.1186/1741-7007-8-100. View

12.

Delivani P, Adrain C, Taylor R, Duriez P, Martin S . Role for CED-9 and Egl-1 as regulators of mitochondrial fission and fusion dynamics. Mol Cell. 2006; 21(6):761-73. DOI: 10.1016/j.molcel.2006.01.034. View

13.

Berman S, Chen Y, Qi B, McCaffery J, Rucker 3rd E, Goebbels S . Bcl-x L increases mitochondrial fission, fusion, and biomass in neurons. J Cell Biol. 2009; 184(5):707-19. PMC: 2686401. DOI: 10.1083/jcb.200809060. View

14.

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

15.

Martins de Brito O, Scorrano L . Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature. 2008; 456(7222):605-10. DOI: 10.1038/nature07534. View

16.

Chen H, Chomyn A, Chan D . Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem. 2005; 280(28):26185-92. DOI: 10.1074/jbc.M503062200. View

17.

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

18.

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

19.

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

20.

Duvezin-Caubet S, Koppen M, Wagener J, Zick M, Israel L, Bernacchia A . OPA1 processing reconstituted in yeast depends on the subunit composition of the m-AAA protease in mitochondria. Mol Biol Cell. 2007; 18(9):3582-90. PMC: 1951777. DOI: 10.1091/mbc.e07-02-0164. View