<p>Genetic and clinical features of COG5 patients.</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.保守寡聚高尔基体（conserved oligomeric Golgi, COG）复合物的亚基COG5，在高尔基体内部的逆行转运过程中发挥关键作用。COG5功能异常与多种人类疾病相关，但其潜在致病机制仍不甚明晰。为探究该机制，我们利用COG5缺陷型及挽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（OXPHOS）缺陷之间的潜在关联。借助COG5缺陷型细胞模型及携带COG5变异体的患者来源细胞，我们通过生化手段验证了COG5在线粒体氧化磷酸化过程中的参与作用，尤其是对复合物I含量的调控。上述模型同时表现出细胞铜水平升高的特征。值得注意的是，无论是恢复COG5的表达，还是施加铜螯合剂，均可显著挽救氧化磷酸化复合物的水平降低现象。我们进一步证实，过量的细胞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，我们发现一例携带双等位基因COG5变异的患者，其临床表现为一种此前未被关联于COG5相关疾病的线粒体疾病亚型——利氏综合征（Leigh syndrome）。本研究为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。我们的研究结果强调了COG5通过铜依赖通路调控线粒体功能的重要性，为理解其在细胞稳态维持及疾病发病机制中的作用提供了新视角。