Department of Chemistry and Biochemistry and the Molecular Biology Institute, University of California, Los Angeles, USA.
MRC Mitochondrial Biology Unit, University of Cambridge, UK.
Free Radic Biol Med. 2020 Jul;154:105-118. doi: 10.1016/j.freeradbiomed.2020.04.029. Epub 2020 May 6.
Coenzyme Q (CoQ) is an essential player in the respiratory electron transport chain and is the only lipid-soluble antioxidant synthesized endogenously in mammalian and yeast cells. In humans, genetic mutations, pathologies, certain medical treatments, and aging, result in CoQ deficiencies, which are linked to mitochondrial, cardiovascular, and neurodegenerative diseases. The only strategy available for these patients is CoQ supplementation. CoQ supplements benefit a small subset of patients, but the poor solubility of CoQ greatly limits treatment efficacy. Consequently, the efficient delivery of CoQ to the mitochondria and restoration of respiratory function remains a major challenge. A better understanding of CoQ uptake and mitochondrial delivery is crucial to make this molecule a more efficient and effective therapeutic tool. In this study, we investigated the mechanism of CoQ uptake and distribution using the yeast Saccharomyces cerevisiae as a model organism. The addition of exogenous CoQ was tested for the ability to restore growth on non-fermentable medium in several strains that lack CoQ synthesis (coq mutants). Surprisingly, we discovered that the presence of CoQ biosynthetic intermediates impairs assimilation of CoQ into a functional respiratory chain in yeast cells. Moreover, a screen of 40 gene deletions considered to be candidates to prevent exogenous CoQ from rescuing growth of the CoQ-less coq2Δ mutant, identified six novel genes (CDC10, RTS1, RVS161, RVS167, VPS1, and NAT3) as necessary for efficient trafficking of CoQ to mitochondria. The proteins encoded by these genes represent essential steps in the pathways responsible for transport of exogenously supplied CoQ to its functional sites in the cell, and definitively associate CoQ distribution with endocytosis and intracellular vesicular trafficking pathways conserved from yeast to human cells.
辅酶 Q（CoQ）是呼吸电子传递链中的重要参与者，也是哺乳动物和酵母细胞中唯一合成的脂溶性抗氧化剂。在人类中，遗传突变、病理、某些医疗治疗和衰老导致 CoQ 缺乏，这与线粒体、心血管和神经退行性疾病有关。这些患者唯一可用的策略是 CoQ 补充。CoQ 补充剂对一小部分患者有益，但 CoQ 的溶解度差极大地限制了治疗效果。因此，有效地将 CoQ 递送到线粒体并恢复呼吸功能仍然是一个主要挑战。更好地了解 CoQ 的摄取和线粒体递呈对于使该分子成为更有效和有效的治疗工具至关重要。在这项研究中，我们使用酵母酿酒酵母作为模型生物，研究了 CoQ 摄取和分布的机制。在缺乏 CoQ 合成（coq 突变体）的几种菌株中，测试了添加外源性 CoQ 恢复在非发酵培养基上生长的能力。令人惊讶的是，我们发现 CoQ 生物合成中间体的存在会损害酵母细胞中将 CoQ 同化到功能性呼吸链中的能力。此外，对 40 个被认为可以防止外源性 CoQ 挽救 CoQ 缺乏的 coq2Δ 突变体生长的基因缺失进行筛选，确定了六个新基因（CDC10、RTS1、RVS161、RVS167、VPS1 和 NAT3）作为 CoQ 有效转运到线粒体所必需的。这些基因编码的蛋白质代表了将外源性供应的 CoQ 运输到其在细胞中的功能部位的途径中的必要步骤，并明确将 CoQ 分布与从酵母到人细胞中保守的内吞作用和细胞内囊泡运输途径相关联。
