Vitamin A as PKC Co-factor and Regulator of Mitochondrial Energetics

For the past century, vitamin A has been considered to serve as a precursor for retinoids that facilitate vision or as a precursor for retinoic acid (RA), a signaling molecule that modulates gene expression. However, vitamin A circulates in plasma at levels that far exceed the amount needed for vision or the synthesis of nanomolar levels of RA, and this suggests that vitamin A alcohol (i.e. retinol) may possess additional biological activity. We have pursued this question for the last 20 years, and in this chapter, we unfold the story of our quest and the data that support a novel and distinct role for vitamin A (alcohol) action. Our current model supports direct binding of vitamin A to the activation domains of serine/threonine kinases, such as protein kinase C (PKC) and Raf isoforms, where it is involved in redox activation of these proteins. Redox activation of PKCs was first described by the founders of the PKC field, but several hurdles needed to be overcome before a detailed understanding of the biochemistry could be provided. Two discoveries moved the field forward. First, was the discovery that the PKCδ isoform was activated by cytochrome c, a protein with oxidoreduction activity in mitochondria. Second, was the revelation that both PKCδ and cytochrome c are tethered to p66Shc, an adapter protein that brings the PKC zinc-finger substrate into close proximity with its oxidizing partner. Detailed characterization of the PKCδ signalosome complex was made possible by the work of many investigators. Our contribution was determining that vitamin A is a vital co-factor required to support an unprecedented redox-activation mechanism. This unique function of vitamin A is the first example of a general system that connects the one-electron redox chemistry of a heme protein (cytochrome c) with the two-electron chemistry of a classical phosphoprotein (PKCδ). Furthermore, contributions to the regulation of mitochondrial energetics attest to biological significance of vitamin A alcohol action.