2. Academic Validation
  3. The IDH1-R132H mutation aggravates cisplatin-induced acute kidney injury by promoting ferroptosis through disrupting NDUFA1 and FSP1 interaction

The IDH1-R132H mutation aggravates cisplatin-induced acute kidney injury by promoting ferroptosis through disrupting NDUFA1 and FSP1 interaction

  • Cell Death Differ. 2024 Sep 22. doi: 10.1038/s41418-024-01381-8.
Kunmei Lai # 1 2 3,  Zhimin Chen # 1 2 3,  Siyi Lin # 1 2 3,  Keng Ye 1 2 3,  Ying Yuan 1 2 3,  Guoping Li 4,  Yankun Song 4,  Huabin Ma 5,  Tak W Mak 6 7,  Yanfang Xu 8 9 10
Affiliations

Affiliations

  • 1 Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
  • 2 Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
  • 3 Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
  • 4 Department of Pathology, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
  • 5 Central Laboratory, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
  • 6 Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada. tmak@uhnres.utoronto.ca.
  • 7 Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SA, China. tmak@uhnres.utoronto.ca.
  • 8 Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China. xuyanfang99@hotmail.com.
  • 9 Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China. xuyanfang99@hotmail.com.
  • 10 Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China. xuyanfang99@hotmail.com.
  • # Contributed equally.
PMID: 39306640 DOI: 10.1038/s41418-024-01381-8
Abstract

The IDH1-R132H mutation is implicated in the development of various tumors. Whether cisplatin, a common chemotherapeutic agent, induces more significant renal toxicity in individuals with the IDH1-R132H mutation remains unclear. In this study, we observed that the IDH1-R132H mutation exacerbates mitochondrial lipid peroxidation and dysfunction in renal tubules, rendering the kidneys more susceptible to cisplatin-induced Ferroptosis. The IDH1-R132H mutation increases methylation of the Ndufa1 promoter, thereby suppressing NDUFA1 transcription and translation. This suppression disrupts NDUFA1's interaction with FSP1, reducing its resistance to cisplatin-induced tubular epithelial cell death. As a consequence, ROS accumulates, lipid peroxidation occurs, and Ferroptosis is triggered, thereby promoting acute kidney injury. In summary, this study elucidates a novel mechanism underlying cisplatin-induced nephrotoxicity and provides valuable insights for the development of personalized treatment strategies for tumor patients carrying the IDH1-R132H mutation.

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