DNA-PKcs interacts with and phosphorylates Fis1 to induce mitochondrial fragmentation in tubular cells during acute kidney injury

Shiyuan Wang, Hang Zhu, Ruibing Li, David Mui, Sam Toan, Xing Chang, Hao Zhou

Research output: Contribution to journalArticlepeer-review

Abstract

The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) regulates cell death. We sought to determine whether DNA-PKcs played a role in the tubular damage that occurs during acute kidney injury (AKI) induced by LPS injection (to mimic sepsis), cisplatin administration, or renal ischemia/reperfusion injury. Although DNA-PKcs normally localizes to the nucleus, we detected cytoplasmic DNA-PKcs in mouse kidney tissues and urinary sediments of human patients with septic AKI. Increased cytoplasmic amounts of DNA-PKcs correlated with renal dysfunction. Tubule cell-specific DNA-PKcs deletion attenuated AKI-mediated tubular cell death and changes in the abundance of various proteins with mitochondrial functions or roles in apoptotic pathways. DNA-PKcs interacted with Fis1 and phosphorylated it at Thr34 in its TQ motif, which increased the affinity of Fis1 for Drp1 and induced mitochondrial fragmentation. Knockin mice expressing a nonphosphorylatable T34A mutant exhibited improved renal function and histological features and reduced mitochondrial fragmentation upon induction of AKI. Phosphorylation of Thr34 in Fis1 was detectable in urinary sediments of human patients with septic AKI and correlated with renal dysfunction. Our findings provide insight into the role of cytoplasmic DNA-PKcs and phosphorylated Fis1 in AKI development.

Original languageEnglish (US)
Article numbereabh1121
JournalScience signaling
Volume15
Issue number725
DOIs
StatePublished - Mar 15 2022

Bibliographical note

Funding Information:
This study was supported by grants from the NSFC (nos. 81900252, 82000537, and 82170241).

Publisher Copyright:
© 2022 The Authors, some rights reserved.

Keywords

  • Acute Kidney Injury/chemically induced
  • Animals
  • DNA/metabolism
  • Humans
  • Kidney/metabolism
  • Membrane Proteins/metabolism
  • Mice
  • Mitochondria/metabolism
  • Mitochondrial Proteins/genetics
  • Protein Kinases/metabolism

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article

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