Our theme is vitamin A in human and animal physiology. We pursue the hypothesis that vitamin A plays essential roles in signal transduction, distinct from the function of the two principal biological derivatives of vitamin A: retinoic acid in transcription and retinaldehyde in vision. The fundamental importance of vitamin A in physiology is best exemplified in mitochondria where vitamin A is a co-regulator of energy homeostasis.
Vitamin A was discovered 100 years ago by biochemists who were studying the nutritional values of various forms of fats and oils. Among the components of corn oil was the yellow, “fat-soluble substance A”, later christened vitamin A, that promoted normal weight gain in chicks. A dozen years later Wolbach and Howe showed in their trailblazing paper how vitamin A was necessary for the healthy development of numerous organs, including the development of lymphoid organs. These findings seemed pertinent to us when we found in the ’90s that the survival of lymphocytes in vitro depended on the presence of vitamin A in the medium. Retinoic acid, the activated form of vitamin A, at the time presumed solely responsible for its physiology, was incapable of supporting cell growth and survival. Thus began our quest for a vitamin A-specific mechanism of action that was independent of the transcription paradigm of retinoic acid. While we initially focused on the immune system, we soon found that vitamin A had much broader functions, potentially affecting every cell in the body.
A search for intracellular receptors of vitamin A netted a dozen proteins with high-affinity binding sites, all members of the super-family of Raf/PKC serine threonine kinases. Even more intriguing, these binding sites localized to the zinc-finger domains that these kinases have in common and that were known to function as activation domains. However, the classic activation pathways via GTP-ras for Raf kinases, or via diacyl-glycerol for PKC, were independent of vitamin A, raising the question of why these binding sites existed and, moreover, were evolutionarily conserved from insects to man. The findings by others that alternate activation pathways via redox action existed brought a breakthrough. We found that vitamin A was required as co-factor and that in vitamin A deficiency kinase function was compromised. Although this should have opened clear paths of inquiry, the sheer complexity of vitamin A deficiency, which damages multiple pathways in its wake, stymied progress. Eventually we learned that anhydroretinol, a presumed antagonist of vitamin A, blocksATP synthesis, and that anhydroretinol-treated cells, unable to cover their energy demands,go into programmed cell death. A new focus on mitochondria promised a “simpler” model and resulted in the current projects: regulation of energy homeostasis, mitochondria-intrinsic pathways that control respiration, the biochemistry of a novel PKCδ signal module, and the function of vitamin A as an electron carrier.