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Mitochondrial src tyrosine kinase interaction with NDUFS3 subunit of complex I of the electron transport chain is responsible for the inhibitory action of IPC on complex I activity upon reperfusion
Author(s) -
Zhou Juan,
McIntosh Rachel,
Zvara David,
Xu Zhelong
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1033.6
Subject(s) - phosphorylation , proto oncogene tyrosine protein kinase src , tyrosine phosphorylation , protein kinase b , tyrosine kinase , chemistry , protein subunit , cardioprotection , microbiology and biotechnology , tyrosine kinase inhibitor , tyrosine , kinase , mapk/erk pathway , genistein , receptor tyrosine kinase , biochemistry , pharmacology , biology , signal transduction , ischemia , endocrinology , medicine , gene , cancer
While ischemic preconditioning (IPC) and other cardioprotective interventions have been proposed to protect the heart by inhibiting mitochondrial metabolism upon reperfusion, the precise mechanism underlying the modulation is poorly understood. We aimed to probe the potential subcellular events leading to the inhibition of the mitochondrial complex I activity by IPC upon reperfusion. Isolated rat hearts were preconditioned by three cycles of 5 min ischemia and 5 min reperfusion prior to 30 min global ischemia. In the control hearts phosphorylation (Y 416 ) of Src tyrosine kinase (SrcTK) was suppressed 10 min after the onset of reperfusion compared to baseline, whereas Akt (Ser473) and ERK (Thr202/Try204) were markedly phosphorylated. IPC markedly enhanced phosphorylation of all these kinases at reperfusion, an effect that was reversed by the nonselective tyrosine kinase inhibitor genistein. IPC prevented the increase in complex I activity upon reperfusion and this was reversed by genistein, indicating a role of SrcTK in the inhibitory effect of IPC complex I activity, indicating that protein tyrosine phosphorylation presumably by SrcTK may account for the action of IPC. In support, mitochondrial SrcTK but not ERK or Akt was co‐immunoprecipitated with complex I. Further experiments revealed that complex I tyrosine phosphorylation by IPC was found only in NDUFS3 [NADH dehydrogenase (ubiquinone) Fe‐S protein 3] subunit, implying that SrcTK may mediate the action of IPC by interacting with NDUFS3. Taken together, these data suggest that SrcTK modulation of NDUFS3 subunit function may be responsible for the inhibitory action of IPC on complex I activity.