Mitofusin 2-containing Mitochondrial-reticular Microdomains Direct Rapid Cardiomyocyte Bioenergetic Responses Via Interorganelle Ca(2+) Crosstalk

Overview

Journal Circ Res

Specialty Cardiology & Vascular Diseases

Date 2012 Jul 11

PMID 22777004

Citations 194

Authors

Yun Chen

Gyorgy Csordas

Casey Jowdy

Timothy G Schneider

Norbert Csordas

Wei Wang

Yingqiu Liu

Michael Kohlhaas

Maxie Meiser

Stefanie Bergem

Jeanne M Nerbonne

Gerald W Dorn 2nd

Christoph Maack

Affiliations

Soon will be listed here.

Abstract

Rationale: Mitochondrial Ca(2+) uptake is essential for the bioenergetic feedback response through stimulation of Krebs cycle dehydrogenases. Close association of mitochondria to the sarcoplasmic reticulum (SR) may explain efficient mitochondrial Ca(2+) uptake despite low Ca(2+) affinity of the mitochondrial Ca(2+) uniporter. However, the existence of such mitochondrial Ca(2+) microdomains and their functional role are presently unresolved. Mitofusin (Mfn) 1 and 2 mediate mitochondrial outer membrane fusion, whereas Mfn2 but not Mfn1 tethers endoplasmic reticulum to mitochondria in noncardiac cells.

Objective: To elucidate roles for Mfn1 and 2 in SR-mitochondrial tethering, Ca(2+) signaling, and bioenergetic regulation in cardiac myocytes.

Methods And Results: Fruit fly heart tubes deficient of the Drosophila Mfn ortholog MARF had increased contraction-associated and caffeine-sensitive Ca(2+) release, suggesting a role for Mfn in SR Ca(2+) handling. Whereas cardiac-specific Mfn1 ablation had no effects on murine heart function or Ca(2+) cycling, Mfn2 deficiency decreased cardiomyocyte SR-mitochondrial contact length by 30% and reduced the content of SR-associated proteins in mitochondria-associated membranes. This was associated with decreased mitochondrial Ca(2+) uptake (despite unchanged mitochondrial membrane potential) but increased steady-state and caffeine-induced SR Ca(2+) release. Accordingly, Ca(2+)-induced stimulation of Krebs cycle dehydrogenases during β-adrenergic stimulation was hampered in Mfn2-KO but not Mfn1-KO myocytes, evidenced by oxidation of the redox states of NAD(P)H/NAD(P)(+) and FADH(2)/FAD.

Conclusions: Physical tethering of SR and mitochondria via Mfn2 is essential for normal interorganelle Ca(2+) signaling in the myocardium, consistent with a requirement for SR-mitochondrial Ca(2+) signaling through microdomains in the cardiomyocyte bioenergetic feedback response to physiological stress.

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References

Deng H, Dodson M, Huang H, Guo M . The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila. Proc Natl Acad Sci U S A. 2008; 105(38):14503-8. PMC: 2567186. DOI: 10.1073/pnas.0803998105. View

Kohlhaas M, Liu T, Knopp A, Zeller T, Ong M, Bohm M . Elevated cytosolic Na+ increases mitochondrial formation of reactive oxygen species in failing cardiac myocytes. Circulation. 2010; 121(14):1606-13. PMC: 2946079. DOI: 10.1161/CIRCULATIONAHA.109.914911. View

ORourke B, Blatter L . Mitochondrial Ca2+ uptake: tortoise or hare?. J Mol Cell Cardiol. 2009; 46(6):767-74. PMC: 4005816. DOI: 10.1016/j.yjmcc.2008.12.011. View

Kane L, Youle R . Mitochondrial fission and fusion and their roles in the heart. J Mol Med (Berl). 2010; 88(10):971-9. DOI: 10.1007/s00109-010-0674-6. View

Huss J, Kelly D . Mitochondrial energy metabolism in heart failure: a question of balance. J Clin Invest. 2005; 115(3):547-55. PMC: 1052011. DOI: 10.1172/JCI24405. View

Chen H, Chan D . Physiological functions of mitochondrial fusion. Ann N Y Acad Sci. 2010; 1201:21-5. DOI: 10.1111/j.1749-6632.2010.05615.x. View

Sharma V, Ramesh V, Franzini-Armstrong C, Sheu S . Transport of Ca2+ from sarcoplasmic reticulum to mitochondria in rat ventricular myocytes. J Bioenerg Biomembr. 2002; 32(1):97-104. DOI: 10.1023/a:1005520714221. View

Maack C, ORourke B . Excitation-contraction coupling and mitochondrial energetics. Basic Res Cardiol. 2007; 102(5):369-92. PMC: 2785083. DOI: 10.1007/s00395-007-0666-z. View

Campello S, Scorrano L . Mitochondrial shape changes: orchestrating cell pathophysiology. EMBO Rep. 2010; 11(9):678-84. PMC: 2933866. DOI: 10.1038/embor.2010.115. View

10.

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

11.

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

12.

Kirichok Y, Krapivinsky G, Clapham D . The mitochondrial calcium uniporter is a highly selective ion channel. Nature. 2004; 427(6972):360-4. DOI: 10.1038/nature02246. View

13.

Wei A, Aon M, ORourke B, Winslow R, Cortassa S . Mitochondrial energetics, pH regulation, and ion dynamics: a computational-experimental approach. Biophys J. 2011; 100(12):2894-903. PMC: 3123977. DOI: 10.1016/j.bpj.2011.05.027. View

14.

Chen Y, Liu Y, Dorn 2nd G . Mitochondrial fusion is essential for organelle function and cardiac homeostasis. Circ Res. 2011; 109(12):1327-31. PMC: 3237902. DOI: 10.1161/CIRCRESAHA.111.258723. View

15.

Archer S . The mitochondrion as a Swiss army knife: implications for cardiovascular disease. J Mol Med (Berl). 2010; 88(10):963-5. DOI: 10.1007/s00109-010-0665-7. View

16.

Chen Y, Lewis W, Diwan A, Cheng E, Matkovich S, Dorn 2nd G . Dual autonomous mitochondrial cell death pathways are activated by Nix/BNip3L and induce cardiomyopathy. Proc Natl Acad Sci U S A. 2010; 107(20):9035-42. PMC: 2889094. DOI: 10.1073/pnas.0914013107. View

17.

Molkentin J, Robbins J . With great power comes great responsibility: using mouse genetics to study cardiac hypertrophy and failure. J Mol Cell Cardiol. 2008; 46(2):130-6. PMC: 2644412. DOI: 10.1016/j.yjmcc.2008.09.002. View

18.

Gaussin V, van de Putte T, Mishina Y, Hanks M, Zwijsen A, Huylebroeck D . Endocardial cushion and myocardial defects after cardiac myocyte-specific conditional deletion of the bone morphogenetic protein receptor ALK3. Proc Natl Acad Sci U S A. 2002; 99(5):2878-83. PMC: 122441. DOI: 10.1073/pnas.042390499. View

19.

Balaban R . Domestication of the cardiac mitochondrion for energy conversion. J Mol Cell Cardiol. 2009; 46(6):832-41. PMC: 3177846. DOI: 10.1016/j.yjmcc.2009.02.018. View

20.

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