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Mol Cell Biol. 2015 Jan;35(1):211-23. doi: 10.1128/MCB.01054-14. Epub 2014 Oct 27.

Dynamics of mitochondrial DNA nucleoids regulated by mitochondrial fission is essential for maintenance of homogeneously active mitochondria during neonatal heart development.

Author information

1
Department of Protein Biochemistry, Institute of Life Science, Kurume University, Kurume, Japan.
2
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.
3
Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan.
4
Department of Medicine, Division of Cardiovascular Medicine, Kurume University School of Medicine, Kurume, Japan.
5
Cardiovascular Research Institute, Kurume University, Kurume, Japan.
6
Faculty of Life and Environmental Sciences, University of Tsukuba, Ibaraki, Japan.
7
Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan.
8
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.
9
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.
10
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.

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.

PMID:
25348719
PMCID:
PMC4295379
DOI:
10.1128/MCB.01054-14
[Indexed for MEDLINE]
Free PMC Article

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