PGAM5 exacerbates acute renal injury by initiating mitochondria-dependent apoptosis by facilitating mitochondrial cytochrome c release

• Published in: Acta pharmacologica Sinica 2024-01, Vol.45 (1), p.125-136
• Main Authors: Li, Jing-yao, Sun, Xi-ang, Wang, Xin, Yang, Ning-hao, Xie, Hong-yan, Guo, Heng-jiang, Lu, Li, Xie, Xin, Zhou, Li, Liu, Jun, Zhang, Wei, Lu, Li-min
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Immunology; Internal Medicine; Medical Microbiology; Pharmacology/Toxicology; Vaccine
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-023-01151-1

Acute kidney injury (AKI) is a worldwide public health problem characterized by the massive loss of tubular cells. However, the precise mechanism for initiating tubular cell death has not been fully elucidated. Here, we reported that phosphoglycerate mutase 5 (PGAM5) was upregulated in renal tubular epithelial cells during ischaemia/reperfusion or cisplatin-induced AKI in mice. PGAM5 knockout significantly alleviated the activation of the mitochondria-dependent apoptosis pathway and tubular apoptosis. Apoptosis inhibitors alleviated the activation of the mitochondria-dependent apoptosis pathway. Mechanistically, as a protein phosphatase, PGAM5 could dephosphorylate Bax and facilitate Bax translocation to the mitochondrial membrane. The translocation of Bax to mitochondria increased membrane permeability, decreased mitochondrial membrane potential and facilitated the release of mitochondrial cytochrome c (Cyt c ) into the cytoplasm. Knockdown of Bax attenuated PGAM5 overexpression-induced Cyt c release and tubular cell apoptosis. Our results demonstrated that the increase in PGAM5-mediated Bax dephosphorylation and mitochondrial translocation was implicated in the development of AKI by initiating mitochondrial Cyt c release and activating the mitochondria-dependent apoptosis pathway. Targeting this axis might be beneficial for alleviating AKI.