Identification of molecular subtypes and a prognostic risk model based on mitochondrial dynamic related genes in clear cell renal cell carcinoma

Background: Clear cell renal cell carcinoma (ccRCC) represents the most prevalent histological subtype and primary contributor to unfavorable prognosis in renal cancer. While mitochondrial dynamics serve as a critical quality control mechanism linked to tumor malignancy, their clinical significance and specific mechanisms in ccRCC remain poorly understood. Methods: Consnsuclusterplus was used to consensus clustering and molecular subtype screening, Kaplan-Meier analysis was used to analyze survival in different subtypes. PINK1 expression was detected by westernblot, and CCK8 is used to detect cell activity. Immunofluorescence staining of LC3 for evaluating mitochondrial autophagy levels. Results: In this study, we classified 534 ccRCC samples, identified from the UCSC XENA database, into A and B clusters based on 42 mitochondrial dynamic related genes. Cluster A demonstrated superior survival outcomes compared to cluster B. Subsequent analysis revealed significant inter-cluster differences in gene expression profiles, mutational spectra, and immune infiltration patterns. We established a mitochondrial dynamics-related prognostic model incorporating PINK1, NIPSNAP1, and MTFR2, with mitophagy-associated genes represented by PINK1 showing particular prognostic significance in ccRCC. Gene Ontology (GO) analysis indicated significant enrichment of mitophagy pathways in cluster A. Functional investigations demonstrated that PINK1-overexpressing cells exhibited increased sensitivity to sunitinib (lower IC50 values), whereas PINK1 knockdown conferred therapeutic resistance. Western blot and immunofluorescence analyses confirmed elevated mitophagy levels in PINK1-overexpressing cells under sunitinib treatment, contrasting with diminished mitophagy in PINK1-deficient cells. Conclusions: Our findings advance the understanding of mitochondrial dynamics in ccRCC progression, demonstrating that PINK1-mediated enhancement of mitophagy critically potentiates the anti-tumor effects of sunitinib in ccRCC.