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Targeting Mitochondrial Complex I Protects Against Palmitic Acid-Induced Endothelial Dysfunction
Chenxia Zhou1, Da Chen1, Ruoxuan Li1
1Department of Endocrinology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Diabetes, Obesity & Metabolism
|August 9, 2026
Summary
Targeting mitochondrial Complex I may treat endothelial dysfunction caused by high free fatty acids. Modulating Complex I activity reduces mitochondrial oxidative stress and improves vascular health in diabetes and obesity.
Area of Science:
- Biochemistry
- Cell Biology
- Vascular Biology
Background:
- Elevated free fatty acids cause endothelial dysfunction, a key factor in diabetic macrovascular complications.
- Mitochondrial reactive oxygen species (mtROS) mediate lipotoxic injury, but Complex I's role is unclear.
Purpose of the Study:
- To investigate targeting mitochondrial Complex I as a therapy for lipotoxicity-induced endothelial injury.
- To elucidate the role of Complex I dynamics and redox regulation in this process.
Main Methods:
- In vitro studies used palmitic acid-treated human aortic endothelial cells.
- In vivo studies utilized high-fat diet-fed mice.
- Interventions included rotenone (Complex I inhibitor) and NDUFS4-targeting siRNA.
Main Results:
- Palmitic acid induced endothelial dysfunction and increased mtROS via Complex I.
- Modulating Complex I (rotenone or NDUFS4 knockdown) reduced mtROS, improved NAD+/NADH balance, and enhanced endothelial function.
- In vivo, rotenone improved metabolic disturbances, vascular oxidative stress, and endothelial responses.
Conclusions:
- Dysregulated mitochondrial Complex I activity contributes to lipotoxic endothelial injury.
- Complex I modulation is a potential strategy against free fatty acid-induced endothelial dysfunction in metabolic diseases.
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