The review focuses on the role of vitamin A (retinol) in the control of energy homeostasis, and on the manner in which certain retinoids subvert this process, leading potentially to disease. In eukaryotic cells, the pyruvate dehydrogenase complex (PDHC) is negatively regulated by four pyruvate dehydrogenase kinases (PDKs) and two antagonistically acting pyruvate dehydrogenase phosphatases (PDPs). The second isoform, PDK2, is regulated by an autonomous mitochondrial signal cascade that is anchored on protein kinase Cδ (PKCδ), where retinoids play an indispensible co-factor role. Along with its companion proteins p66Shc, cytochrome c, and vitamin A, the PKCδ/retinol complex is located in the intermembrane space of mitochondria. At this site, and in contrast to cytosolic locations, PKCδ is activated by the site-specific oxidation of its cysteine-rich activation domain (CRD) that is configured into a complex RING-finger. Oxidation involves the transfer of electrons from cysteine moieties to oxidized cytochrome c, a step catalyzed by vitamin A. The PKCδ/retinol signalosome monitors the internal cytochrome c redox state that reflects the workload of the respiratory chain. Upon sensing demands for energy PKCδ signals the PDHC to increase glucose-derived fuel flux entering the KREBS cycle. Conversely, if excessive fuel flux surpasses the capacity of the respiratory chain, threatening the release of damaging reactive oxygen species (ROS), the polarity of the cytochrome c redox system is reversed, resulting in the chemical reduction of the PKCδ CRD, restoration of the RING-finger, refolding of PKCδ into the inactive, globular form, and curtailment of PDHC output, thereby constraining the respiratory capacity within safe margins. Several retinoids, notably anhydroretinol and fenretinide, capable of displacing retinol from binding sites on PKCδ, can co-activate PKCδ signaling but, owing to their extended system of conjugated double bonds, are unable to silence PKCδ in a timely manner. Left in the ON position, PKCδ causes chronic overload of the respiratory chain leading to mitochondrial dysfunction. This review explores how defects in the PKCδ signal machinery potentially contribute to metabolic and degenerative diseases.

该综述重点关注维生素 A（视黄醇）在控制能量稳态中的作用，以及某些类视黄醇破坏这一过程并可能导致疾病的方式。在真核细胞中，丙酮酸脱氢酶复合物 (PDHC) 受到四种丙酮酸脱氢酶激酶 (PDK) 和两种拮抗作用的丙酮酸脱氢酶磷酸酶 (PDP) 的负调节。第二种异构体 PDK2 受到锚定于蛋白激酶 Cδ (PKCδ) 上的自主线粒体信号级联的调节，其中类维生素A发挥着不可或缺的辅助因子作用。 PKCδ/视黄醇复合物与其伴随蛋白 p66Shc、细胞色素c和维生素 A 一起位于线粒体的膜间隙中。与胞质位置相反，在该位点，PKCδ 通过其富含半胱氨酸的激活结构域 (CRD) 的位点特异性氧化而被激活，CRD 被配置为复杂的环指。氧化涉及电子从半胱氨酸部分转移到氧化的细胞色素c ，这是维生素 A 催化的一个步骤。PKCδ/视黄醇信号体监测反映呼吸链工作负荷的内部细胞色素c氧化还原状态。在感应到能量需求后，PKCδ 向 PDHC 发出信号，以增加进入 KREBS 循环的葡萄糖衍生燃料通量。 相反，如果过多的燃料通量超过了呼吸链的容量，威胁到破坏性活性氧（ROS）的释放，细胞色素c氧化还原系统的极性就会逆转，导致PKCδ CRD的化学还原，恢复RING-finger，PKCδ 重新折叠成不活跃的球状形式，并减少 PDHC 输出，从而将呼吸能力限制在安全范围内。几种类视黄醇，特别是脱水视黄醇和芬维A胺，能够从 PKCδ 上的结合位点取代视黄醇，可以共同激活 PKCδ 信号传导，但由于其扩展的共轭双键系统，无法及时沉默 PKCδ。处于 ON 位置时，PKCδ 会导致呼吸链慢性超负荷，从而导致线粒体功能障碍。本综述探讨了 PKCδ 信号机制的缺陷如何可能导致代谢和退行性疾病。