BackgroundThe purpose of this study was to develop a new prognostic model for osteosarcoma based on cuproptosis-mitochondrion genes. Materials and methodsThe data of osteosarcoma were obtained from TARGET database. By using Cox regression and LASSO regression analysis, a novel risk score was constructed based on cuproptosis-mitochondrion genes. Kaplan-Meier, ROC curve and independent prognostic analyses were performed to validate the risk score in GSE21257 dataset. Then, a predictive nomogram was constructed and further validated by calibration plot, C-index and ROC curve. Based on the risk score, all patients were divided into high-risk and low-risk group. GO and KEGG enrichment, immune correlation and drug sensitivity analyses were performed between groups. Real-time quantitative PCR verified the expression of cuproptosis-mitochondrion prognostic model genes in osteosarcoma. And we explored the function of FDX1 in osteosarcoma by western blotting, CCK8, colony formation assay, wound healing assay and transwell assays. ResultsA total of six cuproptosis-mitochondrion genes (FDX1, COX11, MFN2, TOMM20, NDUFB9 and ATP6V1E1) were identified. A novel risk score and associated prognostic nomogram were constructed with high clinical application value. Strong differences in function enrichment and tumor immune microenvironment were shown between groups. Besides, the correlation of cuproptosis-mitochondrion genes and drug sensitivity were revealed to search for potential therapeutic target. The expression of FDX1, COX11, MFN2, TOMM20 and NDUFB9 at mRNA level was elevated in osteosarcoma cells compared with normal osteoblast hFOB1.19. The mRNA expression level of ATP6V1E1 was decreased in osteosarcoma. Compared with hFOB1.19, western blotting revealed that the expression of FDX1 was significantly elevated in osteosarcoma cells. Functional experiments indicated that FDX1 mainly promoted the migration of osteosarcoma rather than proliferation. ConclusionsWe developed a novel prognostic model of osteosarcoma based on cuproptosis-mitochondrion genes, which provided great guidance in survival prediction and individualized treatment decision making for patients with osteosarcoma.