A novel role for mitochondrial sphingosine-1-phosphate produced by sphingosine kinase-2 in PTP-mediated cell survival during cardioprotection
- 15 October 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Basic Research in Cardiology
- Vol. 106 (6), 1341-1353
- https://doi.org/10.1007/s00395-011-0223-7
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.Keywords
This publication has 68 references indexed in Scilit:
- Blockade of electron transport during ischemia preserves bcl-2 and inhibits opening of the mitochondrial permeability transition poreFEBS Letters, 2011
- Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusionBasic Research in Cardiology, 2010
- Sphingosine‐1‐phosphate produced by sphingosine kinase 2 in mitochondria interacts with prohibitin 2 to regulate complex IV assembly and respirationThe FASEB Journal, 2010
- Translating novel strategies for cardioprotection: the Hatter Workshop RecommendationsBasic Research in Cardiology, 2010
- TNFα protects cardiac mitochondria independently of its cell surface receptorsBasic Research in Cardiology, 2010
- Isolating the segment of the mitochondrial electron transport chain responsible for mitochondrial damage during cardiac ischemiaBiochemical and Biophysical Research Communications, 2010
- Sphingosine Kinase and Sphingosine 1-Phosphate in CardioprotectionJournal of Cardiovascular Pharmacology, 2009
- Combined sphingosine, S1P and ischemic postconditioning rescue the heart after protracted ischemiaBiochemical and Biophysical Research Communications, 2008
- Acidosis, oxygen, and interference with mitochondrial permeability transition pore formation in the early minutes of reperfusion are critical to postconditioning’s successBasic Research in Cardiology, 2008
- Preconditioning and postconditioning: The essential role of the mitochondrial permeability transition poreCardiovascular Research, 2007