Qin Chaoying, Feng Yabo, Wang Junquan, Huang Weicheng, Jiang Liangqi, Li Yang
Department of Neurosurgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan, China.
PET-CT Center, Chenzhou First People's Hospital, Chenzhou 423000, Hunan, China.
Life Sci. 2025 Sep 15;377:123773. doi: 10.1016/j.lfs.2025.123773. Epub 2025 Jun 2.
Low-grade gliomas (LGG) are known for their slow growth yet retain the potential to progress to more aggressive malignancies. Glioma cells are frequently exposed to stressors such as hypoxia, nutrient deprivation, and oxidative stress, which disrupt protein folding within the endoplasmic reticulum (ER), leading to ER stress and activation of the unfolded protein response (UPR). ER stress plays a complex role in glioma initiation, progression, and resistance to chemotherapy. Dysregulated signaling between mitochondria and the ER can further exacerbate ER stress, impacting glioma cell survival and proliferation. Elucidating the molecular mechanisms by which mitochondrial interactions influence ER stress may reveal novel therapeutic targets for LGG treatment.
ER-stress related mitochondrial protein-coding genes (ERSMGs) linked to LGG prognosis were identified using Mitocarta3.0, Genecards, CGGA, and TCGA data. A prognostic model was developed via univariate and LASSO-Cox regression and validated by ROC curves. OMA1's role was assessed through knockdown experiments in LGG cell lines.
Eleven ERSMGs were significantly associated with LGG prognosis. The model achieved reliable predictive accuracy (AUC > 0.6) and stratified patients into high- and low-risk groups with distinct survival rates. High-risk patients exhibited increased sensitivity to SB505124. OMA1 knockdown in LGG cells induced ER stress by promoting mitochondrial fusion, increasing mtROS, ultimately inhibiting cell proliferation and invasion.
This study provides a novel prognostic model based on ERSMGs, offering novel insights into LGG progression and invasion. OMA1-mediated mitochondrial dysfunction and ER stress play critical roles in glioma cell growth and survival, representing potential therapeutic targets.
低级别胶质瘤（LGG）以其生长缓慢而闻名，但仍有进展为更具侵袭性恶性肿瘤的潜力。胶质瘤细胞经常暴露于诸如缺氧、营养剥夺和氧化应激等应激源中，这些应激源会破坏内质网（ER）内的蛋白质折叠，导致内质网应激和未折叠蛋白反应（UPR）的激活。内质网应激在胶质瘤的起始、进展和化疗耐药中发挥着复杂的作用。线粒体与内质网之间失调的信号传导可进一步加剧内质网应激，影响胶质瘤细胞的存活和增殖。阐明线粒体相互作用影响内质网应激的分子机制可能揭示低级别胶质瘤治疗的新靶点。
利用Mitocarta3.0、Genecards、CGGA和TCGA数据鉴定与低级别胶质瘤预后相关的内质网应激相关线粒体蛋白编码基因（ERSMGs）。通过单变量和LASSO-Cox回归建立预后模型，并通过ROC曲线进行验证。通过在低级别胶质瘤细胞系中的敲低实验评估OMA1的作用。
11个ERSMGs与低级别胶质瘤预后显著相关。该模型实现了可靠的预测准确性（AUC>0.6），并将患者分为具有不同生存率的高风险和低风险组。高风险患者对SB505124表现出更高的敏感性。低级别胶质瘤细胞中的OMA1敲低通过促进线粒体融合、增加线粒体活性氧（mtROS）诱导内质网应激，最终抑制细胞增殖和侵袭。
本研究提供了一种基于ERSMGs的新型预后模型，为低级别胶质瘤的进展和侵袭提供了新的见解。OMA1介导的线粒体功能障碍和内质网应激在胶质瘤细胞生长和存活中起关键作用，代表了潜在的治疗靶点。
