Two protein kinase C isoforms, δ and ε, regulate energy homeostasis in mitochondria by transmitting opposing signals to the pyruvate dehydrogenase complex

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 C delta, thereby linking a prominent kinase network to the redox balance of the ETC. Here, we show that activation of PKC epsilon in mitochondria also requires retinol as a cofactor, implying a redox-mechanism. Whereas activated PKC delta transmits a stimulatory signal to the pyruvate dehdyrogenase complex (PDHC), PKC epsilon opposes this signal and inhibits the PDHC. Our results suggest that the balance between PKC delta and epsilon 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 PKC epsilon over PKC delta. 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 PKC delta and PKC epsilon might underlie the injury inflicted on the ischemic myocardium during reperfusion.-Gong, J., Hoyos, B., Acin-Perez, R., Vinogradov, V., Shabrova, E., Zhao, F., Leitges, M., Fischman, D., Manfredi, G., Hammerling, U. Two protein kinase C isoforms, delta and epsilon, regulate energy homeostasis in mitochondria by transmitting opposing signals to the pyruvate dehydrogenase complex. FASEB J. 26, 3537-3549 (2012). www.fasebj.org