Key result
Inhibiting complex I reverse electron transport rescues endothelial function by suppressing mtROS in preclinical models.
Why the study?
Lipotoxicity causes diabetic vascular injury, and while mitochondrial ROS are key, the role of complex I reverse electron transport remained unclear.
Does inhibition of complex I reverse electron transport improve endothelial function in palmitic acid-treated endothelial cells and high-fat diet-fed mice?
Does inhibition of complex I reverse electron transport improve endothelial function in palmitic acid-treated endothelial cells and high-fat diet-fed mice?
Inhibition of complex I-mediated reverse electron transport rescues lipotoxic endothelial injury, identifying it as a potential therapeutic target for diabetic vascular complications.
Suggests RET as lipotoxicity target in diabetic endothelial models; hypothesis-generating and leaves open human translation.
Introduction and Objective: Lipotoxicity causes diabetic vascular injury. While mitochondrial ROS (mtROS) are key, the role of complex I reverse electron transport (RET) is unclear. We aimed to define RET's mechanistic role. Methods: We used palmitic acid (PA)-treated endothelial cells and high-fat diet (HFD)-fed mice. Assays included mtROS, NAD+/NADH, metabolism, and RNA-seq. RET was probed using rotenone and NDUFS4 knockdown. Results: PA caused endothelial dysfunction (↑mtROS, ↓angiogenesis, inflammation). Transcriptomics showed downregulated vascular genes and activated inflammatory pathways. PA lowered NAD+/NADH and upregulated NDUFS4, promoting complex I-RET. Inhibiting RET (rotenone or NDUFS4 knockdown) suppressed mtROS, restored NAD+/NADH balance, and rescued endothelial function. Glycolysis/TCA suppression persisted post-inhibition, indicating metabolic-function dissociation. In vivo, rotenone reduced HFD-induced vascular oxidative stress and improved endothelial integrity and angiogenesis. Conclusion: Complex I-mediated RET is a major driver of lipotoxic endothelial injury. RET inhibition rescues endothelial health despite ongoing metabolic reprogramming, identifying it as a distinct therapeutic target for diabetic vascular complications. Disclosure C. Zhou: None. D. Chen: None. R. Li: None. Z. Li: None. J. Song: None. Funding the Special Care Program for Obesity in Pudong Health Bureau of Shanghai (PWYq2025-01) and Academic Leaders Training Program of Pudong Health Bureau of Shanghai (PWRd2023-03)
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ZHOU et al. (2026) studied Diabetic vascular injury. Complex I reverse electron transport (RET) inhibition (rotenone or NDUFS4 knockdown) vs. Uninhibited PA-treated cells or HFD-fed mice was evaluated on Endothelial dysfunction (mtROS, NAD+/NADH, angiogenesis, inflammation). Inhibiting complex I reverse electron transport with rotenone or NDUFS4 knockdown suppressed mtROS and rescued endothelial function in palmitic acid-treated cells and high-fat diet-fed mice.
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