Sun Jie, Ding Jie, Yue Han, Xu Binbin, Sodhi Akrit, Xue Kang, Ren Hui, Qian Jiang
Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China.
Shenzhen Eye Hospital, Jinan University, Shenzhen, China.
Autophagy. 2025 Jan;21(1):191-209. doi: 10.1080/15548627.2024.2395142. Epub 2024 Sep 12.
Uveal melanoma (UM) is an aggressive intraocular malignancy derived from melanocytes in the uvea tract of the eye. Up to 50% of patients with UM develop distant metastases which is usually fatal within one year; preventing metastases is therefore essential. Metabolic reprogramming plays a critical role in UM progression and metastasis. However, the metabolic phenotype of UM cells in the hypoxic tumor is not well understood. Here, we report that hypoxia-induced BNIP3 reprograms tumor cell metabolism, promoting their survival and metastasis. In response to hypoxia, BNIP3-mediated mitophagy alleviates mitochondrial dysfunction and enhances mitochondrial oxidative phosphorylation (OXPHOS) while simultaneously reducing mitochondrial reactive oxygen species (mtROS) production. This, in turn, impairs HIF1A/HIF-1α protein stability and inhibits glycolysis. Inhibition of mitophagy significantly suppresses BNIP3-induced UM progression and metastasis and . Collectively, these observations demonstrate a novel mechanism whereby BNIP3 promotes UM metabolic reprogramming and malignant progression by mediating hypoxia-induced mitophagy and suggest that BNIP3 could be an important therapeutic target to prevent metastasis in patients with UM. AOD: average optical density; BNIP3: BCL2/adenovirus E1B interacting protein 3; CQ: chloroquine; CoCl: cobalt chloride; GEPIA: Gene Expression Profiling Interactive Analysis; HIF1A: hypoxia inducible factor 1, alpha subunit; IHC: immunohistochemistry; mtROS: mitochondrial reactive oxygen species; NAC: N-acetylcysteine; OCR: oxygen consumption rate; OXPHOS: oxidative phosphorylation; ROS: reactive oxygen species; TCGA: The Cancer Genome Atlas; UM: uveal melanoma.
葡萄膜黑色素瘤（UM）是一种侵袭性眼内恶性肿瘤，起源于眼葡萄膜中的黑素细胞。高达50%的UM患者会发生远处转移，通常在一年内死亡；因此，预防转移至关重要。代谢重编程在UM的进展和转移中起关键作用。然而，低氧肿瘤中UM细胞的代谢表型尚不清楚。在此，我们报告缺氧诱导的BNIP3可重编程肿瘤细胞代谢，促进其存活和转移。在缺氧反应中，BNIP3介导的线粒体自噬减轻线粒体功能障碍，增强线粒体氧化磷酸化（OXPHOS），同时减少线粒体活性氧（mtROS）的产生。这反过来又损害HIF1A/HIF-1α蛋白稳定性并抑制糖酵解。抑制线粒体自噬可显著抑制BNIP3诱导的UM进展和转移。总的来说，这些观察结果证明了一种新机制，即BNIP3通过介导缺氧诱导的线粒体自噬促进UM代谢重编程和恶性进展，并表明BNIP3可能是预防UM患者转移的重要治疗靶点。AOD：平均光密度；BNIP3：BCL2/腺病毒E1B相互作用蛋白3；CQ：氯喹；CoCl：氯化钴；GEPIA：基因表达谱交互式分析；HIF1A：缺氧诱导因子1α亚基；IHC：免疫组织化学；mtROS：线粒体活性氧；NAC：N-乙酰半胱氨酸；OCR：氧消耗率；OXPHOS：氧化磷酸化；ROS：活性氧；TCGA：癌症基因组图谱；UM：葡萄膜黑色素瘤
