# COG5 deficiency disrupts cellular copper homeostasis and underlies the impaired mitochondrial OXPHOS function

## TL;DR

COG5 deficiency causes copper overload and mitochondrial dysfunction, leading to energy production defects and a new form of Leigh syndrome.

## Contribution

Identifies COG5's role in copper homeostasis and mitochondrial function, revealing a novel pathogenic mechanism and potential therapeutic target.

## Key findings

- COG5 deficiency disrupts ATP7A stability, leading to cellular copper overload.
- Excess copper impairs mitochondrial iron-sulfur clusters and complex I assembly.
- Copper chelation rescues mitochondrial dysfunction in COG5-deficient models.

## Abstract

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, a subunit of the Conserved Oligomeric Golgi (COG) complex, is critical for maintaining Golgi structure and function. While its established role in glycosylation explains some congenital disorders, the full spectrum of associated pathologies remains unclear. COG5 directly interacts with and stabilizes the copper exporter ATP7A. Our study demonstrates that COG5 deficiency disrupts this interaction, leading to reduced ATP7A stability and consequent cellular copper overload. This copper accumulation impairs mitochondrial function by disrupting iron-sulfur cluster biogenesis, resulting in complex I deficiency and energy production defects. Using patient-derived cells with COG5 variants, we validated this pathogenic cascade in a Leigh syndrome case, expanding the clinical spectrum of COG5-related disorders. Significantly, copper chelation reversed these metabolic abnormalities, confirming copper dysregulation as the central pathogenic mechanism. Our work identifies the COG5-ATP7A interaction as a critical regulatory module for copper homeostasis, whose disruption causes mitochondrial dysfunction, revealing a potential target for treating COG5-related disorders.