Mitochondrial DNA stress promotes the ferroptosis of endothelial cells in diabetic peripheral neuropathy via upregulating ALOX15

Diabetic peripheral neuropathy (DPN) is a diabetic complication, featured by impaired vascular functions. This study investigates the roles of arachidonate 15-lipoxygenase (ALOX15) in DPN. High glucose (HG) is used to establish in vitro DPN model. mRNA levels are detected using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Protein expression is detected using Western blot. The release of MDA, GSH, and iron is detected using ELISA assays. Mitochondrial functions are detected using immunofluorescence. Cell viability is detected using CCK-8 assay. Cell proliferation is detected using colony formation. Vascular angiogenesis is detected using tube formation assay. The death of human umbilical vein endothelial cells (HUVECs) is detected using TUNEL staining. The results show that HG treatment increases the release of ox-mtDNA. Ox-mtDNA stress promotes the lipid peroxidation and the accumulation of iron in an ALOX15-depedent manner, resulting in the ferroptosis of HUVECs. Moreover, HG treatment suppresses the expression of proliferation and angiogenesis of HUVECs. However, ALOX15 deficiency promotes the proliferation and angiogenesis of HUVECs, as well as suppresses the ox-mtDNA synthesis and ferroptosis. In conclusion, inhibition of ALOX15 suppresses ox-mtDNA synthesis and the ferroptosis of endothelial cells in DPN. Therefore, targeting ALOX15 may be a promising strategy for DPN.