Epsilon PKC increases brain mitochondrial SIRT1 protein levels via heat shock protein 90 following ischemic preconditioning in rats.
Ischemic preconditioning is a neuroprotective mechanism whereby a sublethal ischemic exposure is protective against a subsequent lethal ischemic attack. We previously demonstrated that SIRT1, a nuclear localized stress-activated deacetylase, is vital for ischemic preconditioning neuroprotection. However, a recent study demonstrated that SIRT1 can also localize to the mitochondria. Mitochondrial localized SIRT1 may allow for a direct protection of mitochondria following ischemic preconditioning. The objective of this study was to determine whether ischemic preconditioning increases brain mitochondrial SIRT1 protein levels and to determine the role of PKCɛ and HSP90 in targeting SIRT1 to the mitochondria. Here we report that preconditioning rats, with 2 min of global cerebral ischemia, induces a delayed increase in non-synaptic mitochondrial SIRT1 protein levels which was not observed in synaptic mitochondria. This increase in mitochondrial SIRT1 protein was found to occur only in neuronal cells and was mediated by PKCε activation. Inhibition of HSP90, a protein chaperone involved in mitochondrial protein import, prevented preconditioning induced increases in mitochondrial SIRT1 and PKCε protein. Our work provides new insights into a possible direct role of SIRT1 in modulating mitochondrial function under both normal and stress conditions, and to a possible role of mitochondrial SIRT1 in activating preconditioning induced ischemic tolerance.
Cerebral Vascular Disease Research Laboratories, Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida, United States of America.
John W
JW
Thompson
Kunjan R
KR
Dave
Isabel
I
Saul
Srinivasan V
SV
Narayanan
Miguel A
MA
Perez-Pinzon
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D019194:Ischemic Preconditioning; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D056564:Sirtuin 1 / Q000378:metabolism*
D018841:HSP90 Heat-Shock Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; C497257:Prkce protein, rat; D051744:Protein Kinase C-epsilon; C488368:Sirt1 protein, rat; D056564:Sirtuin 1