Control of oxidative phosphorylation by vitamin A illuminates a fundamental role in mitochondrial energy homoeostasis Journal Article
| Authors: | Acin-Perez, R.; Hoyos, B.; Zhao, F.; Vinogradov, V.; Fischman, D. A.; Harris, R. A.; Leitges, M.; Wongsiriroj, N.; Blaner, W. S.; Manfredi, G.; Hammerling, U. |
| Article Title: | 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 Cδ (PKCδ), without which this enzyme failed to be activated in mitochondria. Furthermore, retinol needed to physically bind PKCδ, because mutation of the retinol binding site rendered PKCδ unresponsive to Rol, while retaining responsiveness to phorbol ester. The PKCδ/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. © FASEB. |
| Keywords: | signal transduction; controlled study; mutation; nonhuman; animal cell; mouse; mammalia; animals; mice; mus; complex formation; animal experiment; vertebrata; binding site; adenosine triphosphate; retinol; retinol deficiency; protein family; homeostasis; respiration; mitochondria; oxygen consumption; bioenergy; energy metabolism; retinoic acid; oxidative phosphorylation; knockout mouse; jurkat cells; phorbol ester; biotransformation; invertebrata; retinal; pyruvate dehydrogenase complex; vitamin a; protein kinase c delta; protein kinase c-delta; intermediary metabolism; retinoid metabolism; lecithin retinol acyltransferase; pyruvate dehydrogenase; pyruvic acid; retinoic acid receptor; citric acid cycle; energy balance; mitochondrial energy transfer; mitochondrial respiration; sensor; mitochondrial proton-translocating atpases; retinoids; vitamin a deficiency |
| Journal Title: | FASEB Journal |
| Volume: | 24 |
| Issue: | 2 |
| ISSN: | 0892-6638 |
| Publisher: | Federation of American Societies for Experimental Biology |
| Date Published: | 2010-02-01 |
| Start Page: | 627 |
| End Page: | 636 |
| Language: | English |
| DOI: | 10.1096/fj.09-142281 |
| PUBMED: | 19812372 |
| PROVIDER: | scopus |
| PMCID: | PMC2812036 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 4" - "Export Date: 20 April 2011" - "CODEN: FAJOE" - "Source: Scopus" |
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