Protein phosphatase 2Aca modulates fatty acid oxidation and glycolysis to determine tubular cell fate and kidney injury

Energy metabolism is crucial in maintaining cellular homeostasis and adapting to stimuli for tubular cells. However, the underlying mechanisms remain largely unknown. Here, we report that PP2Ac alpha was upregulated in damaged tubular cells from patients and animal models with acute or chronic kidney injury. Using in vitro and in vivo model, we demonstrated that PP2Ac alpha induction in damaged tubular cells suppresses fatty acid oxidation and promotes glycolysis, leading to cell death and fibrosis. Mechanistically, we revealed that PP2Ac alpha dephosphorylates ACC through interaction with B56 delta, leading to the regulation of fatty acid oxidation. Furthermore, PP2Ac alpha also dephosphorylates p-Glut1 (Thr478) and suppresses Trim21-mediated Glut1 ubiquitination and degradation, leading to the promotion of glucose intake and glycolysis. Thus, this study adds new insight into the tubular cell metabolic alterations in kidney diseases. PP2Ac alpha may be a promising therapeutic target for kidney injury.