title: Depressing mitochondria-reticulum interactions protects cardiomyocytes from lethal hypoxia-reoxygenation injury.
abstract: BACKGROUND
  Under physiological conditions, Ca(2+) transfer from the endoplasmic reticulum (ER) to mitochondria might occur at least in part at contact points between the 2 organelles and involves the VDAC1/Grp75/IP3R1 complex. Accumulation of Ca(2+) into the mitochondrial matrix may activate the mitochondrial chaperone cyclophilin D (CypD) and trigger permeability transition pore opening, whose role in ischemia/reperfusion injury is well recognized. We questioned here whether the transfer of Ca(2+) from ER to mitochondria might play a role in cardiomyocyte death after hypoxia-reoxygenation.
  
  
  RESULTS
  We report that CypD interacts with the VDAC1/Grp75/IP3R1 complex in cardiomyocytes. Genetic or pharmacological inhibition of CypD in both H9c2 cardiomyoblasts and adult cardiomyocytes decreased the Ca(2+) transfer from ER to mitochondria through IP3R under normoxic conditions. During hypoxia-reoxygenation, the interaction between CypD and the IP3R1 Ca(2+) channeling complex increased concomitantly with mitochondrial Ca(2+) content. Inhibition of either CypD, IP3R1, or Grp75 decreased protein interaction within the complex, attenuated mitochondrial Ca(2+) overload, and protected cells from hypoxia-reoxygenation. Genetic or pharmacological inhibition of CypD provided a similar effect in adult mice cardiomyocytes. Disruption of ER-mitochondria interaction via the downregulation of Mfn2 similarly reduced the interaction between CypD and the IP3R1 complex and protected against hypoxia-reoxygenation injury.
  
  
  CONCLUSIONS
  Our data (1) point to a new role of CypD at the ER-mitochondria interface and (2) suggest that decreasing ER-mitochondria interaction at reperfusion can protect cardiomyocytes against lethal reperfusion injury through the reduction of mitochondrial Ca(2+) overload via the CypD/VDAC1/Grp75/IP3R1 complex.
authors: From INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de médecine Rockefeller et Charles Merieux Lyon-Sud, Lyon (M.P., E.T., P.T., L.G., C.C. Da S., G.T., N.M., E.B., A.D., M.A., J.R., M.O.); INSERM UMR-1046, Université Montpellier 1, Université Montpellier 2, CHU de Montpellier, Montpellier (J.F., A.L.); and Hospices Civils de Lyon, Hôpital Louis Pradel, Service d'Explorations Fonctionnelles Cardiovasculaires and CIC de Lyon, Lyon (N.M., M.O.), France.
authors: Melanie
authors: M
authors: Paillard
authors: Emily
authors: E
authors: Tubbs
authors: Pierre-Alain
authors: PA
authors: Thiebaut
authors: Ludovic
authors: L
authors: Gomez
authors: Jeremy
authors: J
authors: Fauconnier
authors: Claire Crola
authors: CC
authors: Da Silva
authors: Geoffrey
authors: G
authors: Teixeira
authors: Nathan
authors: N
authors: Mewton
authors: Elise
authors: E
authors: Belaidi
authors: Annie
authors: A
authors: Durand
authors: Maryline
authors: M
authors: Abrial
authors: Alain
authors: A
authors: Lacampagne
authors: Jennifer
authors: J
authors: Rieusset
authors: Michel
authors: M
authors: Ovize
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D015687:Cell Hypoxia / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured / Q000378:metabolism; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000502:physiology*; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology; D066298:In Vitro Techniques; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000502:physiology; D007425:Intracellular Membranes / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000502:physiology*; D046912:Multiprotein Complexes; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D010100:Oxygen / Q000633:toxicity*; D018408:Patch-Clamp Techniques; D011897:Random Allocation; D051381:Rats; D050995:Voltage-Dependent Anion Channel 1 / Q000502:physiology
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D018840:HSP70 Heat-Shock Proteins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008565:Membrane Proteins; D046912:Multiprotein Complexes; C000631446:PPIF protein, mouse; C494764:Vdac1 protein, rat; C018551:glucose-regulated proteins; D050995:Voltage-Dependent Anion Channel 1; D021983:Cyclophilins; D010100:Oxygen
keywords: calcium; ischemia; reperfusion; sarcoplasmic reticulum