title: Mitochondrial fusion dynamics is robust in the heart and depends on calcium oscillations and contractile activity.
abstract: Mitochondrial fusion is thought to be important for supporting cardiac contractility, but is hardly detectable in cultured cardiomyocytes and is difficult to directly evaluate in the heart. We overcame this obstacle through in vivo adenoviral transduction with matrix-targeted photoactivatable GFP and confocal microscopy. Imaging in whole rat hearts indicated mitochondrial network formation and fusion activity in ventricular cardiomyocytes. Promptly after isolation, cardiomyocytes showed extensive mitochondrial connectivity and fusion, which decayed in culture (at 24-48 h). Fusion manifested both as rapid content mixing events between adjacent organelles and slower events between both neighboring and distant mitochondria. Loss of fusion in culture likely results from the decline in calcium oscillations/contractile activity and mitofusin 1 (Mfn1), because (i) verapamil suppressed both contraction and mitochondrial fusion, (ii) after spontaneous contraction or short-term field stimulation fusion activity increased in cardiomyocytes, and (iii) ryanodine receptor-2-mediated calcium oscillations increased fusion activity in HEK293 cells and complementing changes occurred in Mfn1. Weakened cardiac contractility in vivo in alcoholic animals is also associated with depressed mitochondrial fusion. Thus, attenuated mitochondrial fusion might contribute to the pathogenesis of cardiomyopathy.
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107; veisner@bio.puc.cl Gyorgy.Hajnoczky@jefferson.edu.|Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile.
authors.forename: Verónica
authors.initials: V
authors.lastname: Eisner
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Ryan R
authors.identifier: 0000-0001-7639-1923
authors.initials: RR
authors.lastname: Cupo
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140.
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: György
authors.initials: G
authors.lastname: Csordás
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: William S
authors.initials: WS
authors.lastname: Slovinsky
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Melanie
authors.initials: M
authors.lastname: Paillard
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Lan
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140.
authors.forename: Jessica
authors.initials: J
authors.lastname: Ibetti
authors.affiliation: Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada, T2N 4N1.
authors.forename: S R Wayne
authors.initials: SR
authors.lastname: Chen
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140.
authors.forename: J Kurt
authors.initials: JK
authors.lastname: Chuprun
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Jan B
authors.initials: JB
authors.lastname: Hoek
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107; veisner@bio.puc.cl Gyorgy.Hajnoczky@jefferson.edu.
authors.forename: György
authors.initials: G
authors.lastname: Hajnóczky
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D002460:Cell Line; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D008164:Luminescent Proteins / Q000032:analysis / Q000235:genetics; D008297:Male; D018613:Microscopy, Confocal; D008929:Mitochondria, Heart / Q000502:physiology* / Q000648:ultrastructure; D063154:Mitochondrial Dynamics / Q000502:physiology*; D009200:Myocardial Contraction / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014161:Transduction, Genetic
chemical_list: D008164:Luminescent Proteins
keywords: alcohol; calcium; cardiomyopathy; fusion; mitochondria