NDUFV1 activation mediates high glucose-induced apoptosis in peritoneal mesothelial cells

Peritoneal mesothelial cells (PMCs) are critical components of the peritoneum, and prolonged exposure to high glucose in peritoneal dialysis fluid can lead to structural and functional impairment of the peritoneal membrane. However, whether such cellular damage is caused by glucose itself or by the hyperosmotic environment remains controversial.

To elucidate the mechanisms underlying high glucose-induced PMCs apoptosis, we obtain the first dynamic proteomic atlas of HMrSV5 cells under different concentration of glouse and mannitol stimulation. After excluding osmosis, 626 differentially expressed proteins are detected following high glucose stimulation. Notably, the up-regulated differentially expressed proteins are significantly enriched in the oxidative phosphorylation pathway, implicating mitochondrial dysfunction in the apoptotic process. Protein-protein interaction network analysis further reveals that NDUFV1, a core subunit of mitochondrial complex I, might be a key regulator. To validate clinical relevance, we perform a comparative proteomic analysis of peritoneal dialysis effluents from new and long-term peritoneal dialysis patients. The clinical proteomics data reveal a marked enrichment of oxidative phosphorylation in the early-stage of dialysis patients, coinciding with notably up-regulation of NDUFV1. Molecular biology experiments demonstrate that the up-regulation of NDUFV1 increases reactive oxygen species production, disrupted mitochondrial membrane potential, thereby promoting apoptosis.

In summary, our findings indicate that glucose-based peritoneal dialysis primarily induces mitochondrial oxidative phosphorylation mediated apoptosis of PMCs through high glucose, with NDUFV1 serving as a critical mediator in this process. These results provide new insights into the prevention and treatment of peritoneal dialysis related peritoneal injury.