title: Role of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission in oxygen sensing and constriction of the ductus arteriosus.
abstract: BACKGROUND
  Closure of the ductus arteriosus (DA) is essential for the transition from fetal to neonatal patterns of circulation. Initial PO2-dependent vasoconstriction causes functional DA closure within minutes. Within days a fibrogenic, proliferative mechanism causes anatomic closure. Though modulated by endothelial-derived vasodilators and constrictors, O2 sensing is intrinsic to ductal smooth muscle cells and oxygen-induced DA constriction persists in the absence of endothelium, endothelin, and cyclooxygenase mediators. O2 increases mitochondrial-derived H2O2, which constricts ductal smooth muscle cells by raising intracellular calcium and activating rho kinase. However, the mechanism by which oxygen changes mitochondrial function is unknown.
  
  
  OBJECTIVE
  The purpose of this study was to determine whether mitochondrial fission is crucial for O2-induced DA constriction and closure.
  
  
  RESULTS
  Using DA harvested from 30 term infants during correction of congenital heart disease, as well as DA from term rabbits, we demonstrate that mitochondrial fission is crucial for O2-induced constriction and closure. O2 rapidly (<5 minutes) causes mitochondrial fission by a cyclin-dependent kinase- mediated phosphorylation of dynamin-related protein 1 (Drp1) at serine 616. Fission triggers a metabolic shift in the ductal smooth muscle cells that activates pyruvate dehydrogenase and increases mitochondrial H2O2 production. Subsequently, fission increases complex I activity. Mitochondrial-targeted catalase overexpression eliminates PO2-induced increases in mitochondrial-derived H2O2 and cytosolic calcium. The small molecule Drp1 inhibitor, Mdivi-1, and siDRP1 yield concordant results, inhibiting O2-induced constriction (without altering the response to phenylephrine or KCl) and preventing O2-induced increases in oxidative metabolism, cytosolic calcium, and ductal smooth muscle cells proliferation. Prolonged Drp1 inhibition reduces DA closure in a tissue culture model.
  
  
  CONCLUSIONS
  Mitochondrial fission is an obligatory, early step in mammalian O2 sensing and offers a promising target for modulating DA patency.
authors: Department of Medicine, Queen's University, 94 Stuart St, Kingston, Ontario, Canada.
authors: Zhigang
authors: Z
authors: Hong
authors: Shelby
authors: S
authors: Kutty
authors: Peter T
authors: PT
authors: Toth
authors: Glenn
authors: G
authors: Marsboom
authors: James M
authors: JM
authors: Hammel
authors: Carolyn
authors: C
authors: Chamberlain
authors: John J
authors: JJ
authors: Ryan
authors: Hannah J
authors: HJ
authors: Zhang
authors: Willard W
authors: WW
authors: Sharp
authors: Erik
authors: E
authors: Morrow
authors: Kalyani
authors: K
authors: Trivedi
authors: E Kenneth
authors: EK
authors: Weir
authors: Stephen L
authors: SL
authors: Archer
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004373:Ductus Arteriosus / Q000166:cytology / Q000502:physiology*; D034281:Dynamins; D005260:Female; D020558:GTP Phosphohydrolases / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007231:Infant, Newborn; D008297:Male; D008869:Microtubule-Associated Proteins / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000502:physiology*; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D010100:Oxygen / Q000502:physiology*; D010101:Oxygen Consumption / Q000502:physiology; D011817:Rabbits; D046509:Tissue Culture Techniques; D014661:Vasoconstriction / Q000502:physiology*; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D006861:Hydrogen Peroxide; D054460:rho-Associated Kinases; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins; D010100:Oxygen; D002118:Calcium