Critical involvement of PRELID2 in the regulation of mitochondrial homeostasis in renal carcinogenesis

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.