However, the detailed molecular mechanisms and roles of mitochondrial fission in vivo, especially in the developing heart, remain to be revealed. Further, other roles of mitochondrial fission were analyzed by RNA interference (RNAi), expression of the dominant negative form of Drp1 in cultured cardiomyocytes, or administration of Drp1 inhibitor Mdivi-1 to mice, which revealed that the ablation of mitochondrial fission can have protective effects against stress caused by hypoxia and ischemia-reperfusion ( 23, 24). Mitochondrial fission is also important for heart function, as a point mutation in mouse Drp1 causes cardiomyopathy ( 22). Defects in this process lead to mitophagy deficiency that results in accumulation of abnormal mitochondria ( 21). Mfn2 also helps recruit the Parkinson's disease-related E3 ubiquitin ligase Parkin to mitochondria in the heart via phosphorylation by PINK1 (PTEN-induced putative kinase protein 1). Heart-specific Mfn1/2 double-knockout (DKO) mice showed lethality by heart failure, exhibiting respiratory dysfunction and mitochondrial fragmentation/swelling ( 19, 20). However, recent research has demonstrated that factors involved in mitochondrial dynamics also participate in heart function. As mitochondria become tightly packed into myofibril bundles, they tend to lose their morphological dynamics ( 16 – 18). Mitochondria are highly enriched in and dispersed throughout the cytoplasm of cardiomyocytes in the heart to guarantee a sustainable energy supply by oxidative phosphorylation ( 14, 15). We and other groups have previously reported that Drp1 is essential for embryonic and neonatal development, as well as neuronal function in humans and mice ( 7 – 10). Mitochondrial fission is regulated by the dynamin-related GTPase protein Drp1 however, the physiological role of mitochondrial fission remains poorly understood, especially in vivo. Mitochondrial fusion is also important for mitochondrial DNA (mtDNA) homeostasis, as deficiency of mitochondrial fusion factors in cultured cells and skeletal muscle results in reduced mtDNA copy numbers and accumulation of mtDNA mutations ( 6) for unknown reasons. Analysis of these mitochondrial fusion factors also revealed a role of intermitochondrial communication in the maintenance of uniformly active mitochondria ( 4, 5). Mitochondrial fusion factors Mfn2 and OPA1 have been isolated as gene products causal of neurodegenerative disorders such as Charcot-Marie-Tooth neuropathy and autosomal dominant optic atrophy, respectively. Mitochondrial fusion is regulated by GTPases such as Mfn1, Mfn2, and OPA1. Mitochondrial morphology is regulated by a balance between fusion and fission, and recent studies have shown that the dynamic features of mitochondria are also important for cellular processes such as apoptosis, reactive oxygen species (ROS) production, Ca 2+ signaling, mitochondrial quality control, and tissue differentiation ( 1 – 3). Mitochondria not only produce energy by oxidative phosphorylation but also play critical roles in metabolism and cellular signaling. Thus, the dynamics of mtDNA nucleoids regulated by mitochondrial fission is required for neonatal cardiomyocyte development by promoting homogeneous distribution of active mitochondria throughout the cardiomyocytes. The functional and structural alteration of mitochondria also led to immature myofibril assembly and defective cardiomyocyte hypertrophy. The Drp1 ablation in heart and primary cultured cardiomyocytes resulted in severe mtDNA nucleoid clustering and led to mosaic deficiency of mitochondrial respiration. The mitochondrial fission GTPase, Drp1, is highly expressed in the developing neonatal heart, and muscle-specific Drp1 knockout (Drp1-KO) mice showed neonatal lethality due to dilated cardiomyopathy. Here, we precisely analyzed the role of mitochondrial fission in vivo. Cardiac myocytes have a specialized cytoplasmic structure where large mitochondria are aligned into tightly packed myofibril bundles however, recent studies have revealed that mitochondrial dynamics also plays an important role in the formation and maintenance of cardiomyocytes. Mitochondria are dynamic organelles, and their fusion and fission regulate cellular signaling, development, and mitochondrial homeostasis, including mitochondrial DNA (mtDNA) distribution.
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