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
  • 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. [email protected].
  • 7. Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SA, China. [email protected].
  • 8. Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China. [email protected].
  • 9. Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China. [email protected].
  • 10. Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China. [email protected].
  • # 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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