Mitofusin 2-Containing Mitochondrial-Reticular Microdomains Direct Rapid Cardiomyocyte Bioenergetic Responses Via Interorganelle Ca2+ Crosstalk

作者：Chen, Yun; Csordas, Gyorgy; Jowdy, Casey; Schneider, Timothy G.; Csordas, Norbert; Wang, Wei; Liu, Yingqiu; Kohlhaas, Michael; Meiser, Maxie; Bergem, Stefanie; Nerbonne, Jeanne M.; Dom, Gerald W., II; Maack, Christoph^*

来源：Circulation Research, 2012, 111(7): 863-+.

DOI：10.1161/CIRCRESAHA.112.266585

• calcium signaling
• cardiac metabolism
• excitation-contraction coupling
• mitochondria
• redox

Rationale: Mitochondrial Ca2+ 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 Ca2+ uptake despite low Ca2+ affinity of the mitochondrial Ca2+ uniporter. However, the existence of such mitochondrial Ca2+ 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, Ca2+ 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 Ca2+ release, suggesting a role for Mfn in SR Ca2+ handling. Whereas cardiac-specific Mfn1 ablation had no effects on murine heart function or Ca2+ 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 Ca2+ uptake (despite unchanged mitochondrial membrane potential) but increased steady-state and caffeine-induced SR Ca2+ release. Accordingly, Ca2+-induced stimulation of Krebs cycle dehydrogenases during beta-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 Ca2+ signaling in the myocardium, consistent with a requirement for SR-mitochondrial Ca2+ signaling through microdomains in the cardiomyocyte bioenergetic feedback response to physiological stress. (Circ Res. 2012;111:863-875.)

• 出版日期2012-9-14