Control of oxidative phosphorylation by vitamin A illuminates a fundamental role in mitochondrial energy homoeostasis

Abstract

The physiology of two metabolites of vitamin A is understood in substantial detail: retinaldehyde functions as the universal chromophore in the vertebrate and invertebrate eye; retinoic acid regulates a set of vertebrate transcription factors, the retinoic acid receptor superfamily. The third member of this retinoid triumvirate is retinol. While functioning as the precursor of retinaldehyde and retinoic acid, a growing body of evidence suggests a far more fundamental role for retinol in signal transduction. Here we show that retinol is essential for the metabolic fitness of mitochondria. When cells were deprived of retinol, respiration and ATP synthesis defaulted to basal levels. They recovered to significantly higher energy output as soon as retinol was restored to physiological concentration, without the need for metabolic conversion to other retinoids. Retinol emerged as an essential cofactor of protein kinase Cdelta (PKCdelta), without which this enzyme failed to be activated in mitochondria. Furthermore, retinol needed to physically bind PKCdelta, because mutation of the retinol binding site rendered PKCdelta unresponsive to Rol, while retaining responsiveness to phorbol ester. The PKCdelta/retinol complex signaled the pyruvate dehydrogenase complex for enhanced flux of pyruvate into the Krebs cycle. The baseline response was reduced in vitamin A-deficient lecithin:retinol acyl transferase-knockout mice, but this was corrected within 3 h by intraperitoneal injection of vitamin A; this suggests that vitamin A is physiologically important. These results illuminate a hitherto unsuspected role of vitamin A in mitochondrial bioenergetics of mammals, acting as a nutritional sensor. As such, retinol is of fundamental importance for energy homeostasis. The data provide a mechanistic explanation to the nearly 100-yr-old question of why vitamin A deficiency causes so many pathologies that are independent of retinoic acid action.

VARA attenuates hyperoxia-induced impaired alveolar development and lung function in newborn mice

“…However, our study has some limitations. We evaluated important mechanisms associated with abnormal alveolar development (oxidative stress, angiogenesis, cytokines, chemokines, growth factors, and extracellular matrix), but retinoids may affect multiple pathways simultaneously, including those that were not evaluated in this study (1,17,39,47). Experiments using whole lung homogenates do not permit the identification of changes in gene expression or protein synthesis in selected cell populations in vivo, such as airway epithelia, endothelial VARA, 10:1 molar combination of vitamin A (the nutrient) and all-trans retinoic acid (the metabolite); n ϭ 3 mice/group.…”

“…Veness-Meehan et al (46) demonstrated that RA treatment of newborn rats improves survival and alveolarization during hyperoxia exposure. The exact mechanisms by which RA attenuates hyperoxia effects in the newborn lung are uncertain, but RA is known to modulate oxidative stress mediators (1,24), proinflammatory mediators (26), and growth factor expression (39), and such mechanisms may be involved in our model. Regardless of the mechanism by which retinoids exert their effect, an increase in lung VA is essential for this benefit.…”

Effects of Pre- and Post-Administration of Vitamin A on the Growth of Refractory Cancers in Xenograft Mice

“…2, 4, 5). Protein modification by retinol 38) or mitochondrial energy homoeostasis, 39) could be one mechanism employed by retinol to affect cancer cells. Currently, elucidation of the mechanisms of retinol's actions, which are distinct and depend on cell type or experimental methods (activity, mRNA or protein expression etc.)…”

Retinol induces morphological alterations and proliferative focus formation through free radical-mediated activation of multiple signaling pathways

“…It was observed both in cell cultures and animal models [10,52] that retinol-induced oxidative stress is caused by the administration of concentrations above the reported physiological limit, which would increase the availability of this molecule to take part in oxidation-reduction cycles inside cells. On the other hand, it was recently reported that retinol is able to induce the mitochondrial activity by enhancing pyruvate dehydrogenase activity through a nongenomic mechanism of PKC activation, thus resulting in increased free radical formation [53] . This would explain why increased concentrations of retinol induce reactive species production in both cell cultures and animal models.…”