The mitochondrial PKCδ/retinol signal complex exerts real-time control on energy homeostasis.

The review focuses on the role of vitamin A (retinol) in the control of energy homeostasis, and on the manner in which certain retinoids subvert this process, leading potentially to disease. In eukaryotic cells, the pyruvate dehydrogenase complex (PDHC) is negatively regulated by four pyruvate dehydrogenase kinases (PDKs) and two antagonistically acting pyruvate dehydrogenase phosphatases (PDPs). The second isoform, PDK2, is regulated by an autonomous mitochondrial signal cascade that is anchored on protein kinase Cδ (PKCδ), where retinoids play an indispensible co-factor role. Along with its companion proteins p66Shc, cytochrome c, and vitamin A, the PKCδ/retinol complex is located in the intermembrane space of mitochondria. At this site, and in contrast to cytosolic locations, PKCδ is activated by the site-specific oxidation of its cysteine-rich activation domain (CRD) that is configured into a complex RING-finger. Oxidation involves the transfer of electrons from cysteine moieties to oxidized cytochrome c, a step catalyzed by vitamin A. The PKCδ/retinol signalosome monitors the internal cytochrome c redox state that reflects the workload of the respiratory chain. Upon sensing demands for energy PKCδ signals the PDHC to increase glucose-derived fuel flux entering the KREBS cycle. Conversely, if excessive fuel flux surpasses the capacity of the respiratory chain, threatening the release of damaging reactive oxygen species (ROS), the polarity of the cytochrome c redox system is reversed, resulting in the chemical reduction of the PKCδ CRD, restoration of the RING-finger, refolding of PKCδ into the inactive, globular form, and curtailment of PDHC output, thereby constraining the respiratory capacity within safe margins. Several retinoids, notably anhydroretinol and fenretinide, capable of displacing retinol from binding sites on PKCδ, can co-activate PKCδ signaling but, owing to their extended system of conjugated double bonds, are unable to silence PKCδ in a timely manner. Left in the ON position, PKCδ causes chronic overload of the respiratory chain leading to mitochondrial dysfunction. This review explores how defects in the PKCδ signal machinery potentially contribute to metabolic and degenerative diseases.