OPA1 supports mitochondrial dynamics and immune evasion to CD8⁺ T cell in lung adenocarcinoma

Abstract

Background Mitochondrial fusion and fission were identified to play key roles during multiple biology process. Thus, we aim to investigate the roles of OPA1 in mitochondria fusion and immune evasion of non-small cell lung cancer cells. Methods The transcriptional activation of genes related to mitochondrial dynamics was determined by using multi-omics data in lung adenocarcinoma (LUAD). We elucidated the molecular mechanism and roles of OPA1 promoting lung cancer through single-cell sequencing and molecular biological experiments. Results Here, we found that copy number amplification of OPA1 and MFN1 were co-occurring and synergistically activated in tumor epithelial cells in lung cancer tissues. Both of OPA1 and MFN1 were highly expressed in LUAD tumor tissues and OPA1 high expression was associated with poor prognosis. In terms of mechanism, the damaged mitochondria activated the apoptotic signaling pathways, inducing cell cycle arrest and cell apoptosis. More interestingly, OPA1 deficiency damaged mitochondrial dynamics and further blocked the respiratory function to increase the sensitivity of tumor epithelial to CD8+ T cells in non-small cell lung cancer. Conclusions Our study demonstrated the high co-occurrence of copy number amplification and co-expression of OPA1 and MFN1 in LUAD tissue, and further revealed the contribution of OPA1 in maintaining the mitochondria respiratory function and the ability of immune evasion to CD8+ T cells of LUAD.

The identification of novel biomarkers offers potential avenues for therapeutic interventions in lung adenocarcinoma

“…Lung adenocarcinoma, the second most prevalent cancer worldwide and a leading cause of cancerrelated mortality [1], still exhibits a relatively low 5-year survival rate despite extensive research [21]. Numerous studies have demonstrated the involvement of mitochondrial fusion and division in various cellular processes [12] that are closely associated with tumor initiation and progression [13]. Furthermore, mitochondrial gene instability and dysfunction have emerged as novel markers for cancer development [14,15].…”

Ovarian Cancer: A Landscape of Mitochondria with Emphasis on Mitochondrial Dynamics

“…The proteins that participate in mitochondrial fusion and fission process can define a phenotype that protects the cells from apoptosis, as shown in the condition of FIS1 and DRP1 downregulation, MFN1 and MFN2 overexpression [ 101 ] and increased levels of OPA1 [ 26 ]. In particular, enhanced OPA1 protein level can favour its own oligomerization at the cristae junction to reduce the cristae width at the junction, decreasing or delaying the release of apoptogenic molecules into the cytoplasm [ 26 , 102 ].…”

Multi-omics analysis of the oncogenic role of optic atrophy 1 in human cancer

“…Consequently, mitochondrial dynamics play a pivotal role in maintaining mitochondrial quality [ 25 ]. Some researchers found that mitochondrial fusion was significantly increased in the tissues of patients with liver cancer, mitochondrial fusion was also inhibited in liver cancer cell lines after knockdown of OPA1 , and the growth of liver cancer cells cultured in vitro and tumor formation in mice were inhibited [ 26 ]. In LUAD, the mitochondrial fusion process caused by OPA1 is activated, enhancing mitochondrial metabolism to promote tumor growth and inhibit apoptosis.…”