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）在控制能量稳态方面的作用，以及某些类视黄醇破坏这一过程的方式，从而可能导致疾病。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) 和两种具有拮抗作用的丙酮酸脱氢酶磷酸酶 (PDP) 的负调控。第二种同工型 PDK2 受锚定于蛋白激酶 Cδ (PKCδ) 的自主线粒体信号级联调节，其中类视黄醇发挥不可或缺的辅助因子作用。连同其伴随蛋白 p66Shc、细胞色素c和维生素 A，PKCδ/视黄醇复合物位于线粒体的膜间隙。在该位点，与胞质位置相反，PKCδ 被其富含半胱氨酸的激活域 (CRD) 的位点特异性氧化激活，CRD 被配置为复杂的环指。氧化涉及将电子从半胱氨酸部分转移到氧化的细胞色素c，这是由维生素 A 催化的步骤。 PKCδ/视黄醇信号小体监测内部细胞色素c反映呼吸链工作负荷的氧化还原状态。在感知对能量的需求后，PKCδ 向 PDHC 发出信号，以增加进入 KREBS 循环的葡萄糖衍生燃料流量。相反，如果过多的燃料流量超过呼吸链的能力，威胁到破坏性活性氧 (ROS) 的释放，细胞色素c的极性氧化还原系统被逆转，导致 PKCδ CRD 的化学还原，环指的恢复，PKCδ 重新折叠成无活性的球状形式，以及 PDHC 输出的减少，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 上的结合位点置换视黄醇，可以共同激活 PKCδ 信号传导，但由于它们扩展的共轭双键系统，无法及时使 PKCδ 沉默。保留在 ON 位置，PKCδ 导致呼吸链慢性过载，导致线粒体功能障碍。本综述探讨了 PKCδ 信号机制中的缺陷如何潜在地导致代谢和退行性疾病。