Abstract: SA-PO146
The IDH1-R132H Mutation Aggravates Cisplatin-Induced AKI by Promoting Ferroptosis through the Induction of NDUFA1 Methylation
Session Information
- AKI: Metabolism and Cell Death
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Author
- Xu, Yanfang, Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
Background
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.
Methods
We constructed a mouse model with the IDH1-R132H mutation to evaluate renal injury induced by cisplatin exposure. We explored key genes affected by the IDH1-R132H mutation using ferroptosis inhibitors, Reduced Representation Bisulfite Sequencing (RBBS) sequencing, and flow cytometry. Furthermore, we investigated the deeper mechanisms through overexpression and knockout of Ndufa1 and Fsp1.
Results
We revealed that the IDH1-R132H mutation exacerbates mitochondrial lipid peroxidation and dysfunction in renal tubules, rendering the kidneys more susceptible to cisplatin-induced ferroptosis. Further mechanistic investigations revealed that the IDH1-R132H mutation upregulates the methylation level of the NDUFA1, leading to the suppression of NDUFA1, disrupting the interaction between NDUFA1 and FSP1, resulting in the accumulation of lipid peroxidation and ferroptosis, thereby promoting AKI.
Conclusion
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.
IDH1-R132H mutation aggravates cisplatin-Induced AKI
(A, B) The IDH1-R132H mutation exacerbates kidney injury, which can be partially reversed by the ferroptosis inhibitor Lip-1. (C, D) IDH1-R132H mutation increases mitochondrial lipid peroxidation. (E) IDH1-R132H mutation leads to an upregulation of NDUFA1 methylation levels. (F) There is a direct interaction between NDUFA1 and FSP1. (G) Overexpression of FSP1 exerts a protective effect.
Funding
- Government Support – Non-U.S.