Exploring necrosis-associated mitochondrial gene signatures: revealing their role in prognosis and immunotherapy of renal clear cell carcinoma

Abstract

AbstractMitochondrial dysfunction and necrotic apoptosis, pivotal in therapeutic strategies for multiple diseases, lack comprehensive understanding in the context of renal clear cell carcinoma (ccRCC). This study explores their potential as valuable tools for ccRCC prediction, prevention, and personalized medical care. Transcriptomic and clinical datasets were acquired from the Cancer Genome Atlas (TCGA) repository. Mitochondrial and necrosis-associated gene sets were sourced from MitoCarta3.0 and the KEGG Pathway databases, respectively. Six necrosis-related mitochondrial genes (nc-MTGs) with prognostic significance were analyzed and screened, and a prognostic model was constructed. The accuracy of the model was verified using external data (E-MTAB-1980). TISCH was used to explore nc-MTGs at the cellular level. Finally, the expression level of BH3 interacting domain death agonist (BID) in ccRCC cell line was detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), and the effect of BID down-regulation on tumor cell migration was verified by transwell assays and wound-healing experiments. We established and validated a prognostic model for clear cell renal cell carcinoma (ccRCC) utilizing six necrosis-related mitochondrial genes (nc-MTGs), affirming its efficacy in evaluating tumor progression. RT-PCR results showed that BID expression was up-regulated in ccRCC tissues compared with controls and exhibited oncogenic effects. In vitro cell function experiments showed that BID may be an important factor affecting the migration of ccRCC. Our study is the first to elucidate the biological functions and prognostic significance of mitochondrial molecules related to necroptosis, providing a new way to evaluate mitochondrial therapeutics in patients with ccRCC.