Pyruvate kinase M2 regulates mitochondrial homeostasis in cisplatin-induced acute kidney injury

• Published in: Cell death & disease 2023-10, Vol.14 (10), p.663-663, Article 663
• Main Authors: Xie, Wenjia, He, Qingyun, Zhang, Yan, Xu, Xinxin, Wen, Ping, Cao, Hongdi, Zhou, Yang, Luo, Jing, Yang, Junwei, Jiang, Lei
• Format: Article
• Language: English
• Subjects: 13/106; 13/2; 13/51; 13/89; 14/1; 631/80/82/23; 64/60; 692/699/1585/4; 82/58; 82/80; Antibodies; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell death; Cell survival; Cisplatin; Dynamin; Epithelial cells; Ferroptosis; Glycolysis; Homeostasis; Immunology; Kidneys; Kinases; Life Sciences; Mitochondria; Myosin; Necroptosis; Phosphorylation; Pyruvate kinase; Pyruvic acid; Staurosporine
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-023-06195-z

An important pathophysiological process of acute kidney injury (AKI) is mitochondrial fragmentation in renal tubular epithelial cells, which leads to cell death. Pyruvate kinase M2 (PKM2) is an active protein with various biological functions that participates in regulating glycolysis and plays a key role in regulating cell survival. However, the role and mechanism of PKM2 in regulating cell survival during AKI remain unclear. Here, we found that the phosphorylation of PKM2 contributed to the formation of the PKM2 dimer and translocation of PKM2 into the mitochondria after treatment with staurosporine or cisplatin. Mitochondrial PKM2 binds myosin heavy chain 9 (MYH9) to promote dynamin-related protein 1 (DRP1)-mediated mitochondrial fragmentation. Both in vivo and in vitro, PKM2-specific loss or regulation PKM2 activity partially limits mitochondrial fragmentation, alleviating renal tubular injury and cell death, including apoptosis, necroptosis, and ferroptosis. Moreover, staurosporine or cisplatin-induced mitochondrial fragmentation and cell death were reversed in cultured cells by inhibiting MYH9 activity. Taken together, our results indicate that the regulation of PKM2 abundance and activity to inhibit mitochondrial translocation may maintain mitochondrial integrity and provide a new therapeutic strategy for treating AKI.