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.