Mitofusin 2-containing mitochondrial-reticular microdomains direct rapid cardiomyocyte bioenergetic responses via interorganelle Ca(2+) crosstalk.
Mitofusin 2-containing mitochondrial-reticular microdomains direct rapid cardiomyocyte bioenergetic responses via interorganelle Ca(2+) crosstalk.
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DOI：
10.1161/circresaha.112.266585
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发表时间：
2012-09-14
影响因子：
20.1
通讯作者：
Maack C
中科院分区：
文献类型：
--
作者：
Chen Y;Csordás G;Jowdy C;Schneider TG;Csordás N;Wang W;Liu Y;Kohlhaas M;Meiser M;Bergem S;Nerbonne JM;Dorn GW 2nd;Maack C
线粒体Ca ~（2+）摄取是通过刺激Krebs循环酶的生物能量反馈反应所必需的。线粒体与肌浆网（SR）的密切联系可以解释尽管线粒体Ca 2+单向转运体的Ca 2+亲和力低，但线粒体Ca 2+摄取效率高。然而，这种线粒体Ca 2+微结构域的存在及其功能作用目前尚未解决。线粒体融合蛋白（Mfn）1和2介导线粒体外膜融合，而Mfn 2，而不是Mfn 1，在非心脏细胞中将内质网拴系到线粒体。阐明Mfn 1和2在心肌细胞SR-线粒体拴系、Ca 2+信号和生物能量调节中的作用。果蝇心管缺乏果蝇Mfn直系同源物，MARF，增加了收缩相关的和咖啡因敏感的Ca 2+释放，这表明Mfn在SR Ca 2+处理中的作用。虽然心脏特异性Mfn 1消融对小鼠心脏功能或Ca 2+循环没有影响，但Mfn 2缺乏使心肌细胞SR-线粒体接触长度减少了30%，并降低了心肌细胞相关膜中SR相关蛋白的含量。这与线粒体Ca 2+摄取减少有关（尽管线粒体膜电位不变），但增加了稳态和咖啡因诱导的SR Ca 2+释放。因此，在β-肾上腺素能刺激期间，Ca 2+诱导的Krebs循环酶刺激在Mfn 2-而非Mfn 1-KO肌细胞中受到阻碍，这通过NAD（P）H/NAD（P）+和FADH 2/FAD的氧化还原状态的氧化得到证明。通过Mfn 2对SR和线粒体进行物理束缚对于心肌中正常的细胞器间Ca 2+信号传导至关重要，这与心肌细胞对生理应激的生物能反馈反应中通过微域进行SR-线粒体Ca 2+信号传导的要求一致。
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, while Mfn2, but not Mfn1, tethers endoplasmic reticulum to mitochondria in non-cardiac cells. To elucidate roles for Mfn1 and 2 in SR-mitochondrial tethering, Ca2+ signaling and bioenergetic regulation in cardiac myocytes. 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. While 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 β-adrenergic stimulation was hampered in Mfn2-, but not Mfn1-KO myocytes, evidenced by oxidation of the redox states of NAD(P)H/NAD(P)+ and FADH2/FAD. Physical tethering of SR and mitochondria via Mfn2 is essential for normal inter-organelle 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.