<p>Underlying numerical data.</p>

COG5, a subunit of the conserved oligomeric Golgi (COG) complex, plays a critical role in retrograde trafficking within the Golgi apparatus. Dysfunction of COG5 is associated with various human disorders, yet the underlying pathogenic mechanisms remain poorly understood. To investigate the mechanisms, we conducted proteomic analyses using COG5-deficient and rescue cell models, which revealed a potential link between COG5 dysfunction and mitochondrial oxidative phosphorylation (OXPHOS) deficiency. Using COG5-deficient cell models and patient-derived cells harboring COG5 variants, we biochemically validated the involvement of COG5 in mitochondrial OXPHOS, particularly in the regulation of complex I content. These models also exhibited elevated cellular copper levels. Notably, the significant reduction in OXPHOS complexes could be rescued by either restoring COG5 expression or administering a copper chelator. We further demonstrated that excessive cellular copper disrupts the function of mitochondrial iron-sulfur clusters, potentially leading to complex I assembly defects. Additionally, we identified a patient with biallelic COG5 variants presenting with a distinct subtype of mitochondrial disease (Leigh syndrome), a phenotype not previously associated with COG5-related disorders. These findings provide novel mechanistic insights into the role of COG5, extending beyond its established function in Golgi-mediated glycosylation modifications. Our results underscore the importance of COG5 in mitochondrial function through a copper-dependent pathway, offering new perspectives on its contribution to cellular homeostasis and disease pathogenesis.COG5作为保守寡聚高尔基体复合物（conserved oligomeric Golgi complex, COG）的一个亚基，在高尔基体内的逆向运输过程中发挥关键作用。COG5功能异常与多种人类疾病相关，但其潜在的致病机制仍不甚明晰。为探究该致病机制，本研究利用COG5缺陷及拯救细胞模型开展蛋白质组学分析，结果揭示了COG5功能异常与线粒体氧化磷酸化（mitochondrial oxidative phosphorylation, OXPHOS）缺陷之间的潜在关联。借助COG5缺陷细胞模型以及携带COG5变异体的患者来源细胞，研究人员通过生化实验验证了COG5参与线粒体氧化磷酸化过程，尤其是对复合物I含量的调控作用。上述模型同时表现出细胞内铜水平升高的表型。值得注意的是，无论是恢复COG5的表达，还是施加铜螯合剂，均能够挽救OXPHOS复合物显著减少这一缺陷。研究团队进一步证实，过量的细胞内铜会破坏线粒体铁硫簇的功能，进而可能导致复合物I组装缺陷。此外，本研究还发现一名携带双等位基因COG5变异体的患者，其临床表现为一种独特的线粒体疾病亚型——利氏综合征（Leigh syndrome），而该表型此前从未被报道与COG5相关疾病存在关联。上述研究结果为COG5的功能提供了全新的机制见解，拓展了其在高尔基体介导的糖基化修饰之外的已知功能。本研究结果强调了COG5通过铜依赖途径在线粒体功能中的重要性，为理解其在细胞稳态及疾病发病机制中的作用提供了新的视角。