Cardiolipin remodeling reflects mitochondrial reprogramming in clear cell renal cell carcinoma

Cardiolipin (CL) is a mitochondria-specific phospholipid essential for maintaining mitochondrial structure and function; however, its role in clear cell renal cell carcinoma (ccRCC) remains unclear. We performed comprehensive phospholipidomic profiling using LC-TQMS on paired tumor and adjacent normal kidney tissues from ccRCC patients, complemented by immunoblotting, immunohistochemistry, and transcriptomic analyses from TCGA and institutional RNA-seq cohorts. CL showed the most pronounced reduction in tumor tissues, accompanied by decreased phosphatidylserine and phosphatidylinositol, whereas phosphatidic acid and phosphatidylglycerol remained unchanged. Reduced CL levels paralleled decreased VDAC1 expression, indicating diminished mitochondrial abundance. Notably, highly unsaturated CL species were preferentially depleted, suggesting oxidative stress-driven remodeling of mitochondrial membranes. Gene expression analysis revealed that the CL remodeling enzyme TAZ was consistently upregulated in both TCGA and institutional datasets. Despite reduced CL content, this apparent paradox suggests that tumor cells actively attempt to restore mitochondrial homeostasis, although these efforts appear insufficient. These findings demonstrate both quantitative and qualitative CL remodeling in ccRCC, reflecting mitochondrial reduction and adaptation to chronic oxidative stress, and highlight a potential metabolic vulnerability.