Targeting Mitochondrial Complex I Protects Against Palmitic Acid–Induced Endothelial Dysfunction
Chenxia Zhou, Da Chen, Ruoxuan Li, Ziyi Li, Xinnan Ji, Yiming Teng, Xiaoyuan Huai, Bo Feng, Jun SongABSTRACT
Background
Endothelial dysfunction induced by elevated free fatty acids is a critical initiating event in diabetic macrovascular complications. While mitochondrial reactive oxygen species (mtROS) are key mediators of this lipotoxic injury, the specific contribution of mitochondrial Complex I dynamics and its associated redox regulation remains to be fully elucidated.
Methods
We investigated the therapeutic potential of targeting mitochondrial Complex I in lipotoxicity‐induced endothelial injury. Using rotenone (a Complex I inhibitor) and NDUFS4 [NADH Dehydrogenase (Ubiquinone) Fe‐S Protein 4]‐targeting siRNA, we performed in vitro interventions in palmitic acid‐treated human aortic endothelial cells and in vivo studies in high‐fat diet (HFD)‐fed mice.
Results
Palmitic acid triggered endothelial dysfunction accompanied by pronounced mitochondrial oxidative stress. Mechanistically, palmitic acid lowered the oxidised/reduced nicotinamide adenine dinucleotide (NAD + /NADH) ratio and increased NADH‐linked Complex I activity, a redox state consistent with enhanced Complex I‐linked ROS generation. Pharmacological (rotenone) or genetic ( NDUFS4 knockdown) modulation of Complex I activity suppressed mtROS overproduction, improved NAD + /NADH balance, alleviated oxidative stress and improved endothelial function. In vivo, rotenone attenuated HFD‐induced systemic metabolic disturbances and vascular oxidative stress while improving endothelial barrier integrity and angiogenic responses.
Conclusions
Our study suggests that dysregulated mitochondrial Complex I activity may serve as an important contributor to lipotoxic endothelial injury. These findings support Complex I modulation as a potential strategy to mitigate free fatty acid‐induced endothelial dysfunction in obesity‐ and diabetes‐related vascular complications.