Abstract 7302: Critical involvement of PRELID2 in the regulation of mitochondrial homeostasis in renal carcinogenesis

Abstract Background: Mitochondrial homeostasis is critical for tumor adaptation to oxidative stress in clear cell renal cell carcinoma (ccRCC). PRELID2, a mitochondrial intermembrane space protein involved in lipid trafficking, has not been studied in renal carcinogenesis. We identified PRELID2 as a novel regulator of mitochondrial function and potential therapeutic target in ccRCC. Methods: RNA sequencing was performed on 178 ccRCC patient samples. In vitro and in vivo studies established PRELID2's functional roles in ccRCC proliferation and progression. Mitochondrial proteomics, lipidomics (LC-MS), oxidative stress assays, co-immunoprecipitation, and mass spectrometry were conducted for comprehensive analysis. Results: PRELID2 was significantly elevated in ccRCC and correlated with poor prognosis in metastatic cases. Unlike other PRELI family proteins, PRELID2 specifically interacted with Prohibitin 2 (PHB2), a mitochondrial scaffolding protein. PRELID2 depletion increased mitochondrial oxidative stress, resulting in elevated oxidized peptides and reduced cytochrome c under stress conditions. Lipidomics revealed altered phosphatidylglycerol composition, a cardiolipin precursor. Xenograft experiments showed PRELID2 overexpression significantly enhanced tumor growth. Conclusion: PRELID2 is a critical regulator of mitochondrial lipid homeostasis and oxidative stress resistance in ccRCC. The PRELID2-PHB2 interaction represents a potential therapeutic target for novel interventions in renal tumorigenesis. Citation Format: Renpei Kato, Daiki Ikarashi, Shigekatsu Maekawa, Mitsugu Kanehira, Yosuke Matsushita, Tetsuro Yoshimaru, Tomoya Fukawa, Toyomasa Katagiri, Wataru Obara. Critical involvement of PRELID2 in the regulation of mitochondrial homeostasis in renal carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7302.