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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 C\u03b4 (PKC\u03b4), without which this enzyme failed to be activated in mitochondria. Furthermore, retinol needed to physically bind PKC\u03b4, because mutation of the retinol binding site rendered PKC\u03b4 unresponsive to Rol, while retaining responsiveness to phorbol ester. The PKC\u03b4\/retinol complex signaled the pyruvate dehydrogenase complex for enhanced flux of pyruvate into the Krebs cycle. The baseline response was reduced in vitamin A\u2010deficient lecithin:retinol acyl transferase\u2010knockout mice, but this was corrected within 3h 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\u2010yr\u2010old question of why vitamin A deficiency causes so many pathologies that are independent of retinoic acid action.\u2014Acin\u2010Perez, T., Hoyos, B., Zhao, F., Vinogradov, V., Fischman, D. A., Harris, R. A., Leitges, M., Wongsiriroj, N., Blaner, W. S., Manfredi, G., Hammerling, U. Control of oxidative phosphorylation by vitamin A illuminates a fundamental role in mitochondrial energy homoeostasis.\n                    <jats:italic>FASEB J<\/jats:italic>\n                    . 24, 627\u2013636 (2010).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.09-142281","type":"journal-article","created":{"date-parts":[[2009,10,7]],"date-time":"2009-10-07T22:20:17Z","timestamp":1254954017000},"page":"627-636","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Control of oxidative phosphorylation by vitamin A illuminates a fundamental role in mitochondrial energy homoeostasis"],"prefix":"10.1096","volume":"24","author":[{"given":"Rebeca","family":"Acin\u2010Perez","sequence":"first","affiliation":[{"name":"Department of Neurology and Neurobiology Weill\u2010Cornell Medical School New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Hoyos","sequence":"additional","affiliation":[{"name":"Immunology Program Sloan\u2010Kettering Institute for Cancer Research New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Immunology Program Sloan\u2010Kettering Institute for Cancer Research New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Vinogradov","sequence":"additional","affiliation":[{"name":"Immunology Program Sloan\u2010Kettering Institute for Cancer Research New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald A.","family":"Fischman","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology Weill\u2010Cornell Medical School New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Harris","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Indiana University School of Medicine Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Leitges","sequence":"additional","affiliation":[{"name":"Biotechnology Center of Oslo University of Oslo Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuttaporn","family":"Wongsiriroj","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biosciences University of Graz Graz Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William S.","family":"Blaner","sequence":"additional","affiliation":[{"name":"Department of Human Nutrition and Department of Medicine College of Physicians and Surgeons Columbia University New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Manfredi","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurobiology Weill\u2010Cornell Medical School New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Hammerling","sequence":"additional","affiliation":[{"name":"Immunology Program Sloan\u2010Kettering Institute for Cancer Research New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,10,7]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)88553-2"},{"key":"e_1_2_6_3_1","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/S0021-9258(18)88530-1","article-title":"The relation of growth to the chemical constitutents of the diet","volume":"145","author":"Osborne T. B.","year":"1913","journal-title":"J. Biol. Chem."},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0168-9525(88)90108-4"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(88)90522-3"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.162.3850.230"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.192.6.835"},{"key":"e_1_2_6_8_1","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1096\/fj.00-0329fje","article-title":"Retinoids as ligands and coactivators of protein kinase C alpha","volume":"15","author":"Imam A.","year":"2001","journal-title":"FASEB J."},{"key":"e_1_2_6_9_1","doi-asserted-by":"crossref","first-page":"2521","DOI":"10.1242\/jcs.112.15.2521","article-title":"F\u2010actin as a functional target for retro\u2010retinoids: a potential role in anhydroretinol\u2010triggered cell death","volume":"112","author":"Korichneva I.","year":"1999","journal-title":"J. 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