title: Dynamics of mitochondrial DNA nucleoids regulated by mitochondrial fission is essential for maintenance of homogeneously active mitochondria during neonatal heart development.
abstract: Mitochondria are dynamic organelles, and their fusion and fission regulate cellular signaling, development, and mitochondrial homeostasis, including mitochondrial DNA (mtDNA) distribution. 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. Here, we precisely analyzed the role of mitochondrial fission in vivo. 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. The Drp1 ablation in heart and primary cultured cardiomyocytes resulted in severe mtDNA nucleoid clustering and led to mosaic deficiency of mitochondrial respiration. The functional and structural alteration of mitochondria also led to immature myofibril assembly and defective cardiomyocyte hypertrophy. 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.
authors.affiliation: Department of Protein Biochemistry, Institute of Life Science, Kurume University, Kurume, Japan.
authors.forename: Takaya
authors.initials: T
authors.lastname: Ishihara
authors.affiliation: Department of Protein Biochemistry, Institute of Life Science, Kurume University, Kurume, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Ban-Ishihara
authors.affiliation: Department of Protein Biochemistry, Institute of Life Science, Kurume University, Kurume, Japan Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Maeda
authors.affiliation: Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Matsunaga
authors.affiliation: Department of Protein Biochemistry, Institute of Life Science, Kurume University, Kurume, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Ichimura
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kyogoku
authors.affiliation: Cardiovascular Research Institute, Kurume University, Kurume, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Aoki
authors.affiliation: Faculty of Life and Environmental Sciences, University of Tsukuba, Ibaraki, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Katada
authors.affiliation: Faculty of Life and Environmental Sciences, University of Tsukuba, Ibaraki, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nakada
authors.affiliation: Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Nomura
authors.affiliation: Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Mizushima
authors.affiliation: Department of Protein Biochemistry, Institute of Life Science, Kurume University, Kurume, Japan Department of Molecular Biology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Mihara
authors.affiliation: Department of Protein Biochemistry, Institute of Life Science, Kurume University, Kurume, Japan Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan ishihara_naotada@kurume-u.ac.jp.
authors.forename: Naotada
authors.initials: N
authors.lastname: Ishihara
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics*; D004195:Disease Models, Animal; D034281:Dynamins / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000378:metabolism; D032342:Muscle Cells / Q000166:cytology; D032383:Myocytes, Cardiac / Q000166:cytology; D010101:Oxygen Consumption; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C486391:Dnm1l protein, mouse; D034281:Dynamins