Department of Biology, University of Waterloo, Waterloo, ON N2L 3G1, Canada.
Waterloo Institute for Nanotechnology, University of Waterloo, Waterloo, ON N2L 3G1, Canada.
Int J Mol Sci. 2024 Mar 29;25(7):3814. doi: 10.3390/ijms25073814.
Inherited defects in cytochrome oxidase (COX) are associated with a substantial subset of diseases adversely affecting the structure and function of the mitochondrial respiratory chain. This multi-subunit enzyme consists of 14 subunits and numerous cofactors, and it requires the function of some 30 proteins to assemble. COX assembly was first shown to be the primary defect in the majority of COX deficiencies 36 years ago. Over the last three decades, most COX assembly genes have been identified in the yeast , and studies in yeast have proven instrumental in testing the impact of mutations identified in patients with a specific COX deficiency. The advent of accessible genome-wide sequencing capabilities has led to more patient mutations being identified, with the subsequent identification of several new COX assembly factors. However, the lack of genotype-phenotype correlations and the large number of genes involved in generating a functional COX mean that functional studies must be undertaken to assign a genetic variant as being causal. In this review, we provide a brief overview of the use of yeast as a model system and briefly compare the COX assembly process in yeast and humans. We focus primarily on the studies in yeast that have allowed us to both identify new COX assembly factors and to demonstrate the pathogenicity of a subset of the mutations that have been identified in patients with inherited defects in COX. We conclude with an overview of the areas in which studies in yeast are likely to continue to contribute to progress in understanding disease arising from inherited COX deficiencies.
细胞色素 c 氧化酶 (COX) 的遗传缺陷与大量结构和功能不良的疾病相关，这些疾病会对线粒体呼吸链产生不利影响。这种多亚基酶由 14 个亚基和许多辅因子组成，需要 30 多种蛋白质的功能才能组装。36 年前首次表明 COX 组装是大多数 COX 缺乏症的主要缺陷。在过去的三十年中，大多数 COX 组装基因已在酵母中被鉴定，并且在酵母中的研究对于测试在具有特定 COX 缺乏症的患者中鉴定出的突变的影响至关重要。可访问的全基因组测序能力的出现导致更多的患者突变被识别，随后鉴定出了几种新的 COX 组装因子。然而，缺乏基因型-表型相关性以及涉及生成功能性 COX 的大量基因意味着必须进行功能研究，以将遗传变异指定为因果关系。在这篇综述中，我们简要概述了使用酵母作为模型系统的情况，并简要比较了酵母和人类中的 COX 组装过程。我们主要关注在酵母中的研究，这些研究使我们能够鉴定新的 COX 组装因子，并证明在具有 COX 遗传缺陷的患者中鉴定出的一部分突变的致病性。最后我们概述了在酵母中的研究可能继续为理解遗传性 COX 缺陷引起的疾病的进展做出贡献的领域。
