Bhandari Poonam, Song Moshi, Dorn Gerald W
Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
J Mol Cell Cardiol. 2015 Mar;80:71-80. doi: 10.1016/j.yjmcc.2014.12.018. Epub 2014 Dec 30.
Mitochondrial dynamism (fusion and fission) is responsible for remodeling interconnected mitochondrial networks in some cell types. Adult cardiac myocytes lack mitochondrial networks, and their mitochondria are inherently "fragmented". Mitochondrial fusion/fission is so infrequent in cardiomyocytes as to not be observable under normal conditions, suggesting that mitochondrial dynamism may be dispensable in this cell type. However, we previously observed that cardiomyocyte-specific genetic suppression of mitochondrial fusion factors optic atrophy 1 (Opa1) and mitofusin/MARF evokes cardiomyopathy in Drosophila hearts. We posited that fusion-mediated remodeling of mitochondria may be critical for cardiac homeostasis, although never directly observed. Alternately, we considered that inner membrane Opa1 and outer membrane mitofusin/MARF might have other as-yet poorly described roles that affect mitochondrial and cardiac function. Here we compared heart tube function in three models of mitochondrial fragmentation in Drosophila cardiomyocytes: Drp1 expression, Opa1 RNAi, and mitofusin MARF RNA1. Mitochondrial fragmentation evoked by enhanced Drp1-mediated fission did not adversely impact heart tube function. In contrast, RNAi-mediated suppression of either Opa1 or mitofusin/MARF induced cardiac dysfunction associated with mitochondrial depolarization and ROS production. Inhibiting ROS by overexpressing superoxide dismutase (SOD) or suppressing ROMO1 prevented mitochondrial and heart tube dysfunction provoked by Opa1 RNAi, but not by mitofusin/MARF RNAi. In contrast, enhancing the ability of endoplasmic/sarcoplasmic reticulum to handle stress by expressing Xbp1 rescued the cardiomyopathy of mitofusin/MARF insufficiency without improving that caused by Opa1 deficiency. We conclude that decreased mitochondrial size is not inherently detrimental to cardiomyocytes. Rather, preservation of mitochondrial function by Opa1 located on the inner mitochondrial membrane, and prevention of ER stress by mitofusin/MARF located on the outer mitochondrial membrane, are central functions of these "mitochondrial fusion proteins".
线粒体动力学（融合与分裂）负责重塑某些细胞类型中相互连接的线粒体网络。成年心肌细胞缺乏线粒体网络，其线粒体本质上是“碎片化”的。线粒体融合/分裂在心肌细胞中极为罕见，在正常条件下无法观察到，这表明线粒体动力学在这种细胞类型中可能是可有可无的。然而，我们之前观察到，果蝇心脏中线粒体融合因子视神经萎缩蛋白1（Opa1）和线粒体融合蛋白/MARF的心肌细胞特异性基因抑制会引发心肌病。我们推测，尽管从未直接观察到，但融合介导的线粒体重塑可能对心脏稳态至关重要。或者，我们认为线粒体内膜的Opa1和外膜的线粒体融合蛋白/MARF可能还有其他尚未充分描述的作用，这些作用会影响线粒体和心脏功能。在这里，我们比较了果蝇心肌细胞中三种线粒体碎片化模型的心脏管功能：Drp1表达、Opa1 RNA干扰和线粒体融合蛋白MARF RNA干扰。由增强的Drp1介导的分裂引起的线粒体碎片化并未对心脏管功能产生不利影响。相比之下，RNA干扰介导的Opa1或线粒体融合蛋白/MARF的抑制会诱导与线粒体去极化和活性氧产生相关的心脏功能障碍。通过过表达超氧化物歧化酶（SOD）抑制活性氧或抑制ROMO1可预防由Opa1 RNA干扰引发的线粒体和心脏管功能障碍，但不能预防由线粒体融合蛋白/MARF RNA干扰引发的功能障碍。相反，通过表达Xbp1增强内质网/肌浆网应对压力的能力，可挽救线粒体融合蛋白/MARF功能不足引起的心肌病，但不能改善由Opa1缺乏引起的心肌病。我们得出结论，线粒体大小减小本身对心肌细胞并无损害。相反，线粒体内膜上的Opa1对线粒体功能的维持以及线粒体外膜上的线粒体融合蛋白/MARF对内质网应激的预防是这些“线粒体融合蛋白”的核心功能。
