Control of oxidative phosphorylation by vitamin A illuminates a fundamental role in mitochondrial energy homoeostasis
Control of oxidative phosphorylation by vitamin A illuminates a fundamental role in mitochondrial energy homoeostasis
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DOI：
10.1096/fj.09-142281
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发表时间：
2010-02-01
期刊：
影响因子：
4.8
通讯作者：
Hammerling, Ulrich
中科院分区：
文献类型：
--
作者：
Acin-Perez, Rebeca;Hoyos, Beatrice;Hammerling, Ulrich
维生素A的两种代谢物的生理学被理解得相当详细：视黄醇在脊椎动物和无脊椎动物眼中作为通用发色团发挥作用;视黄酸调节一组脊椎动物转录因子，视黄酸受体超家族。这类维生素A三巨头的第三个成员是视黄醇。虽然作为视黄醇和视黄酸的前体发挥作用，但越来越多的证据表明视黄醇在信号转导中起着更重要的作用。在这里，我们表明，视黄醇是必不可少的线粒体的代谢健身。当细胞被剥夺了视黄醇，呼吸和ATP合成默认为基础水平。一旦视黄醇恢复到生理浓度，它们就恢复到显着更高的能量输出，而不需要代谢转化为其他类维生素A。视黄醇作为蛋白激酶C δ（PKC δ）的一种重要辅因子出现，没有它，这种酶在线粒体中不能被激活。此外，视黄醇需要物理结合PKC δ，因为视黄醇结合位点的突变使得PKC δ对Rol无反应，而保留对佛波酯的反应性。PKC δ/视黄醇复合物向丙酮酸脱氢酶复合物发出信号，以增强丙酮酸进入克雷布斯循环的通量。维生素A缺乏的卵磷脂：视黄醇酰基转移酶基因敲除小鼠的基线反应降低，但这在3小时内通过腹腔注射维生素A得到纠正;这表明维生素A在生理上是重要的。这些结果阐明了维生素A在哺乳动物线粒体生物能量学中迄今未被怀疑的作用，作为营养传感器。因此，视黄醇对能量平衡至关重要。这些数据为近100年的问题提供了一个机械解释，即为什么维生素A缺乏会导致如此多的不依赖于视黄酸作用的病理。Acin-Perez，T.，Hoyos，B.，赵芳，维诺格拉多夫，V. Fischman，D.一、哈里斯河，巴西-地一、Leitges，M.，Wongsiriroj，N.，Blaner，W.美国，Manfredi，G.，哈默林大学维生素A对氧化磷酸化的控制阐明了线粒体能量稳态的基本作用。FASEB J.24，627-636（2010）。www.fasebj.org
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 C delta (PKC delta), without which this enzyme failed to be activated in mitochondria. Furthermore, retinol needed to physically bind PKC delta, because mutation of the retinol binding site rendered PKC delta unresponsive to Rol, while retaining responsiveness to phorbol ester. The PKC delta/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.-Acin-Perez, 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. FASEB J. 24, 627-636 (2010). www.fasebj.org