Ascorbate uptake enables tubular mitophagy to prevent septic AKI by PINK1-PARK2 axis

• Published in: Biochemical and biophysical research communications 2021-05, Vol.554, p.158-165
• Main Authors: Chen, Zhi-Dong, Hu, Bang-Chuan, Shao, Xue-Ping, Hong, Jun, Zheng, Yang, Zhang, Run, Shao, Zi-Qiang, Liu, Jin-Quan, Yang, Xiang-Hong, Sun, Ren-Hua, Mo, Shi-Jing
• Format: Article
• Language: English
• Subjects: Ascorbate; Mitophagy; PINK1-PARK2 axis; Septic AKI
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2021.03.103

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. •TLR4 activation by LPS stimuli enhances ascorbate uptake in a Fn14/SCFFbxw7α-dependent manner.•Ascorbate uptake efficiently prevents the LPS-inducible tubular apoptosis mediated by PINK1-PARK2 axis.•Ascorbate uptake renders tubular mitophagy upon LPS stimuli.•Administration of high-dose ascorbate confers mitophagy and protects mice from septic AKI.