title: MARF and Opa1 control mitochondrial and cardiac function in Drosophila.
abstract: BACKGROUND
  Mitochondria interact via actions of outer and inner membrane fusion proteins. The role of mitochondrial fusion in functioning of the heart, where mitochondria comprise ≈30% of cardiomyocyte volume and their intermyofilament spatial arrangement with other mitochondria is highly ordered, is unknown.
  
  
  OBJECTIVE
  Model and analyze mitochondrial fusion defects in Drosophila melanogaster heart tubes with tincΔ4Gal4-directed expression of RNA interference (RNAi) for mitochondrial assembly regulatory factor (MARF) and optic atrophy (Opa)1.
  
  
  RESULTS
  Live imaging analysis revealed that heart tube-specific knockdown of MARF or Opa1 increases mitochondrial morphometric heterogeneity and induces heart tube dilation with profound contractile impairment. Sarcoplasmic reticular structure was unaffected. Cardiomyocyte expression of human mitofusin (mfn)1 or -2 rescued MARF RNAi cardiomyopathy, demonstrating functional homology between Drosophila MARF and human mitofusins. Suppressing mitochondrial fusion increased compensatory expression of nuclear-encoded mitochondrial genes, indicating mitochondrial biogenesis. The MARF RNAi cardiomyopathy was prevented by transgenic expression of superoxide dismutase 1.
  
  
  CONCLUSIONS
  Mitochondrial fusion is essential to cardiomyocyte mitochondrial function and regeneration. Reactive oxygen species are key mediators of cardiomyopathy in mitochondrial fusion-defective cardiomyocytes. Postulated mitochondrial-endoplasmic reticulum interactions mediated uniquely by mfn2 appear dispensable to functioning of the fly heart.
authors.affiliation: Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA. gdorn@dom.wustl.edu
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.forename: Charles F
authors.initials: CF
authors.lastname: Clark
authors.forename: William H
authors.initials: WH
authors.lastname: Eschenbacher
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Kang
authors.forename: John T
authors.initials: JT
authors.lastname: Engelhard
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Warner
authors.forename: Scot J
authors.initials: SJ
authors.lastname: Matkovich
authors.forename: Casey C
authors.initials: CC
authors.lastname: Jowdy
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000096:biosynthesis / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D008561:Membrane Fusion / Q000502:physiology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins; D051336:Mitochondrial Membranes / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D034622:RNA Interference
chemical_list: D029721:Drosophila Proteins; C527117:Marf protein, Drosophila; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; C527116:OPA1 protein, Drosophila; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C470017:Mfn1 protein, human