Mitochondrial fusion dynamics is robust in the heart and depends on calcium oscillations and contractile activity

Eisner, V.; Cupo, R. R.; Gao, E.; Csordas, G.; Slovinsky, W. S.; Paillard, Mélanie; Cheng, L.; Ibetti, J.; Chen, S. R. W.; Chuprun, J. K.; Hoek, J. B.; Koch, W. J.; Hajnoczky, G.

Mitochondrial fusion dynamics is robust in the heart and depends on calcium oscillations and contractile activity

2017

Mitochondrial fusion is thought to be important for supporting cardiac contractility, but is hardly detectable in cultured cardio-myocytes and is difficult to directly evaluate in the heart. We overcame this obstacle through in vivo adenoviral transduction with matrix-targeted photoactivatable GFP and confocal microscopy. Imaging in whole rat hearts indicated mitochondrial network formation and fusion activity in ventricular cardiomyocytes. Promptly after isolation, cardiomyocytes showed extensive mitochondrial connectivity and fusion, which decayed in culture (at 24-48 h). Fusion manifested both as rapid content mixing events between adjacent organelles and slower events between both neighboring and distant mitochondria. Loss of fusion in culture likely results from the decline in calcium oscillations/contractile activity and mitofusin 1 (Mfn1), because (i) verapamil suppressed both contraction and mitochondrial fusion, (ii) after spontaneous contraction or short-term field stimulation fusion activity increased in cardiomyocytes, and (iii) ryanodine receptor-2-mediated calcium oscillations increased fusion activity in HEK293 cells and complementing changes occurred in Mfn1. Weakened cardiac contractility in vivo in alcoholic animals is also associated with depressed mitochondrial fusion. Thus, attenuated mitochondrial fusion might contribute to the pathogenesis of cardiomyopathy.

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