title: Two protein kinase C isoforms, δ and ε, regulate energy homeostasis in mitochondria by transmitting opposing signals to the pyruvate dehydrogenase complex.
abstract: Energy production in mitochondria is a multistep process that requires coordination of several subsystems. While reversible phosphorylation is emerging as the principal tool, it is still unclear how this signal network senses the workloads of processes as different as fuel procurement, catabolism in the Krebs cycle, and stepwise oxidation of reducing equivalents in the electron transfer chain. We previously proposed that mitochondria use oxidized cytochrome c in concert with retinol to activate protein kinase Cδ, thereby linking a prominent kinase network to the redox balance of the ETC. Here, we show that activation of PKCε in mitochondria also requires retinol as a cofactor, implying a redox-mechanism. Whereas activated PKCδ transmits a stimulatory signal to the pyruvate dehdyrogenase complex (PDHC), PKCε opposes this signal and inhibits the PDHC. Our results suggest that the balance between PKCδ and ε is of paramount importance not only for flux of fuel entering the Krebs cycle but for overall energy homeostasis. We observed that the synthetic retinoid fenretinide substituted for the retinol cofactor function but, on chronic use, distorted this signal balance, leading to predominance of PKCε over PKCδ. The suppression of the PDHC might explain the proapoptotic effect of fenretinide on tumor cells, as well as the diminished adiposity observed in experimental animals and humans. Furthermore, a disturbed balance between PKCδ and PKCε might underlie the injury inflicted on the ischemic myocardium during reperfusion. dehydrogenase complex.
authors.affiliation: Immunology Program, Sloan-Kettering Institute for Cancer Research, New York, New York 10065, USA.
authors.forename: Jianli
authors.initials: J
authors.lastname: Gong
authors.forename: Beatrice
authors.initials: B
authors.lastname: Hoyos
authors.forename: Rebeca
authors.initials: R
authors.lastname: Acin-Perez
authors.forename: Valerie
authors.initials: V
authors.lastname: Vinogradov
authors.forename: Elena
authors.initials: E
authors.lastname: Shabrova
authors.forename: Feng
authors.initials: F
authors.lastname: Zhao
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.forename: Donald
authors.initials: D
authors.lastname: Fischman
authors.forename: Giovanni
authors.initials: G
authors.lastname: Manfredi
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hammerling
mesh_terms: D000818:Animals; D002460:Cell Line; D002952:Citric Acid Cycle; D004734:Energy Metabolism / Q000187:drug effects*; D004789:Enzyme Activation; D017313:Fenretinide / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects*; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000187:drug effects / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014801:Vitamin A / Q000378:metabolism; D016335:Zinc Fingers
chemical_list: D011768:Pyruvate Dehydrogenase Complex; D014801:Vitamin A; D017313:Fenretinide; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon