title: A novel role for mitochondrial sphingosine-1-phosphate produced by sphingosine kinase-2 in PTP-mediated cell survival during cardioprotection.
abstract: Although mitochondria are key determinants of myocardial injury during ischemia-reperfusion (I/R), their interaction with critical cytoprotective signaling systems is not fully understood. Sphingosine-1-phosphate (S1P) produced by sphingosine kinase-1 protects the heart from I/R damage. Recently a new role for mitochondrial S1P produced by a second isoform of sphingosine kinase, SphK2, was described to regulate complex IV assembly and respiration via interaction with mitochondrial prohibitin-2. Here we investigated the role of SphK2 in cardioprotection by preconditioning. Littermate (WT) and sphk2                         (-/-) mice underwent 45 min of in vivo ischemia and 24 h reperfusion. Mice received no intervention (I/R) or preconditioning (PC) via 5 min I/R before the index ischemia. Despite the activation of PC-cytoprotective signaling pathways in both groups, infarct size in sphk2                         (-/-) mice was not reduced by PC (42 ± 3% PC vs. 43 ± 4% I/R, p = ns) versus WT (24 ± 3% PC vs. 43 ± 3% I/R, p < 0.05). sphk2                         (-/-) mitochondria exhibited decreased oxidative phosphorylation and increased susceptibility to permeability transition (PTP). Unlike WT, PC did not prevent ischemic damage to electron transport or the increased susceptibility to PTP. To evaluate the direct contribution to the resistance of mitochondria to cytoprotection, SphK2, PHB2 or cytochrome oxidase subunit IV was depleted in cardiomyoblasts. PC protection was abolished by each knockdown concomitant with decreased PTP resistance. These results point to a new action of S1P in cardioprotection and suggest that the mitochondrial S1P produced by SphK2 is required for the downstream protective modulation of PTP as an effector of preconditioning protection.
authors: Department of Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
authors: Ludovic
authors: L
authors: Gomez
authors: Melanie
authors: M
authors: Paillard
authors: Megan
authors: M
authors: Price
authors: Qun
authors: Q
authors: Chen
authors: Geoffrey
authors: G
authors: Teixeira
authors: Sarah
authors: S
authors: Spiegel
authors: Edward J
authors: EJ
authors: Lesnefsky
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019194:Ischemic Preconditioning; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D000091402:Prohibitins; D034741:RNA, Small Interfering; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D014162:Transfection; D000099157:Sphingosine Kinase
chemical_list: D008246:Lysophospholipids; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017853:Phosphotransferases (Alcohol Group Acceptor); D000091402:Prohibitins; D034741:RNA, Small Interfering; D013110:Sphingosine; D000099157:Sphingosine Kinase; C000717333:Phb2 protein, mouse; C060506:sphingosine 1-phosphate