Ascorbate uptake enables tubular mitophagy to prevent septic AKI by PINK1-PARK2 axis.
Ascorbate (Vitamin C) has been proposed as a promising therapeutic agent against sepsis in clinical trials, but there is little experimental evidence on its anti-septic efficacy. We report that Toll-like receptor 4 (TLR4) activation by LPS stimuli augments ascorbate uptake in murine and human tubular cells through upregulation of two ascorbate transporters SVCT-1 and -2 mediated by Fn14/SCFFbxw7α cascade. Ascorbate restriction, or knockout of SVCT-1 and -2, the circumstance reminiscent to blockade of ascorbate uptake, endows tubular cells more vulnerable to the LPS-inducible apoptosis, whereas exogenous administration of ascorbate overrides the ruin execution, for which the PINK1-PARK2, rather than BNIP3-NIX axis is required. Ascorbate increases, while SVCT-1 and -2 knockout or ascorbate restriction dampens tubular mitophagy upon LPS stimuli. Treatment of endotoxemic mice with high-dose ascorbate confers mitophagy and substantial protection against mortality and septic acute kidney injury (AKI). Our work provides a rationale for clinical management of septic AKI with high doses of ascorbate.
['Chen|Zhi-Dong|ZD|', 'Hu|Bang-Chuan|BC|', 'Shao|Xue-Ping|XP|', 'Hong|Jun|J|', 'Zheng|Yang|Y|', 'Zhang|Run|R|', 'Shao|Zi-Qiang|ZQ|', 'Liu|Jin-Quan|JQ|', 'Yang|Xiang-Hong|XH|', 'Sun|Ren-Hua|RH|', 'Mo|Shi-Jing|SJ|']
D058186:Acute Kidney Injury D000818:Animals D001205:Ascorbic Acid D002460:Cell Line D004195:Disease Models, Animal D006801:Humans D007684:Kidney Tubules D008070:Lipopolysaccharides D008297:Male D051379:Mice D008928:Mitochondria D063306:Mitophagy D011494:Protein Kinases D018805:Sepsis D015398:Signal Transduction D044767:Ubiquitin-Protein Ligases D014815:Vitamins
Ascorbate Mitophagy Septic AKI PINK1-PARK2 axis