Regulation of intermediary metabolism by the PKCδ signalosome in mitochondria Journal Article
| Authors: | Acin-Perez, R.; Hoyos, B.; Gong, J.; Vinogradov, V.; Fischman, D. A.; Leitges, M.; Borhan, B.; Starkov, A.; Manfredi, G.; Hammerling, U. |
| Article Title: | Regulation of intermediary metabolism by the PKCδ signalosome in mitochondria |
| Abstract: | PKCδ has emerged as a novel regulatory molecule of oxidative phosphorylation by targeting the pyruvate dehydrogenase complex (PDHC). We showed that activation of PKCδ leads to the dephosphorylation of pyruvate dehydrogenase kinase 2 (PDK2), thereby decreasing PDK2 activity and increasing PDH activity, accelerating oxygen consumption, and augmenting ATP synthesis. However, the molecular components that mediate PKCδ signaling in mitochondria have remained elusive so far. Here, we identify for the first time a functional complex, which includes cytochrome c as the upstream driver of PKCδ, and uses the adapter protein p66Shc as a platform with vitamin A (retinol) as a fourth partner. All four components are necessary for the activation of the PKCδ signal chain. Genetic ablation of any one of the three proteins, or retinol depletion, silences signaling. Furthermore, mutations that disrupt the interaction of cytochrome c with p66Shc, of p66Shc with PKCδ, or the deletion of the retinol-binding pocket on PKCδ, attenuate signaling. In cytochrome c-deficient cells, reintroduction of cytochrome c Fe3+ protein restores PKCδ signaling. Taken together, these results indicate that oxidation of PKCδ is key to the activation of the pathway. The PKCδ/p66Shc/cytochrome c signalosome might have evolved to effect site-directed oxidation of zinc-finger structures of PKCδ, which harbor the activation centers and the vitamin A binding sites. Our findings define the molecular mechanisms underlying the signaling function of PKCδ in mitochondria. © FASEB. |
| Keywords: | signal transduction; genetics; mutation; nonhuman; animal cell; mouse; animals; mice; mice, knockout; cells, cultured; protein protein interaction; enzyme activation; mice, inbred c57bl; regulatory mechanism; protein-serine-threonine kinases; immunoblotting; binding site; multiprotein complexes; retinol; mitochondria; zinc finger protein; oxygen consumption; mitochondrion; oxidative phosphorylation; synthesis; depletion; gene activity; ferric ion; molecule; cytochrome c; energy homeostasis; krebs cycle control; pyruvate dehydrogenase complex; vitamin a; protein kinase c delta; dephosphorylation; enzyme metabolism; cytochromes c; protein kinase c-delta; pyruvate decarboxylase; shc signaling adaptor proteins |
| Journal Title: | FASEB Journal |
| Volume: | 24 |
| Issue: | 12 |
| ISSN: | 0892-6638 |
| Publisher: | Federation of American Societies for Experimental Biology |
| Date Published: | 2010-12-01 |
| Start Page: | 5033 |
| End Page: | 5042 |
| Language: | English |
| DOI: | 10.1096/fj.10-166934 |
| PUBMED: | 20798245 |
| PROVIDER: | scopus |
| PMCID: | PMC2992363 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 20 April 2011" - "CODEN: FAJOE" - "Source: Scopus" |
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