NDUFA5 deficiency promotes renal inflammation in diabetic nephropathy via mitochondrial ROS signaling

Diabetic nephropathy (DN) involves mitochondrial dysfunction, but the role of complex I subunit NDUFA5 is unclear. This study investigated its protective mechanisms. Using tubule-specific Ndufa5 knockout mice, streptozotocin-induced diabetic mice, and high glucose-treated human kidney-2 (HK-2) cells, we assessed the effects of NDUFA5 manipulation. Renal NDUFA5 expression was reduced in diabetes. Its knockout exacerbated mitochondrial damage, ROS overproduction, and renal injury, while AAV9-mediated overexpression ameliorated these defects. NDUFA5 overexpression also suppressed pro-inflammatory cytokines (interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and monocyte chemoattractant protein-1 (MCP-1)) and nuclear factor-κB (NF-κB) signaling in vivo and in vitro. Mechanistically, NDUFA5 attenuated inflammation by inhibiting mitochondrial reactive oxygen species (mtROS) generation. Thus, NDUFA5 protects against DN, at least in part, by preserving mitochondrial integrity and reducing oxidative stress and inflammation, highlighting its potential as a therapeutic target.