BackgroundMitochondria are more than just the powerhouse of cells; they dictate if a cell dies or survives. Mitochondria are dynamic organelles that constantly undergo fusion and fission in response to environmental conditions. We showed previously that mitochondria of cells in a low oxygen environment (hypoxia) hyperfuse to form enlarged or highly interconnected networks with enhanced metabolic efficacy and resistance to apoptosis. Modifications to the appearance and metabolic capacity of mitochondria have been reported in cancer. However, the precise mechanisms regulating mitochondrial dynamics and metabolism in cancer are unknown. Since hypoxia plays a role in the generation of these abnormal mitochondria, we questioned if it modulates mitochondrial function. The mitochondrial outer-membrane voltage-dependent anion channel 1 (VDAC1) is at center stage in regulating metabolism and apoptosis. We demonstrated previously that VDAC1 was post-translationally C-terminal cleaved not only in various hypoxic cancer cells but also in tumor tissues of patients with lung adenocarcinomas. Cells with enlarged mitochondria and cleaved VDAC1 were also more resistant to chemotherapy-stimulated cell death than normoxic cancer cells.ResultsTranscriptome analysis of mouse embryonic fibroblasts (MEF) knocked out for Vdac1 highlighted alterations in not only cancer and inflammatory pathways but also in the activation of the hypoxia-inducible factor-1 (HIF-1) signaling pathway in normoxia. HIF-1α was stable in normoxia due to accumulation of reactive oxygen species (ROS), which decreased respiration and glycolysis and maintained basal apoptosis. However, in hypoxia, activation of extracellular signal-regulated kinase (ERK) in combination with maintenance of respiration and increased glycolysis counterbalanced the deleterious effects of enhanced ROS, thereby allowing Vdac1−/− MEF to proliferate better than wild-type MEF in hypoxia. Allografts of RAS-transformed Vdac1−/− MEF exhibited stabilization of both HIF-1α and HIF-2α, blood vessel destabilization, and a strong inflammatory response. Moreover, expression of Cdkn2a, a HIF-1-target and tumor suppressor gene, was markedly decreased. Consequently, RAS-transformed Vdac1−/− MEF tumors grew faster than wild-type MEF tumors.ConclusionsMetabolic reprogramming in cancer cells may be regulated by VDAC1 through vascular destabilization and inflammation. These findings provide new perspectives into the understanding of VDAC1 in the function of mitochondria not only in cancer but also in inflammatory diseases.

中文翻译：

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敲除 Vdac1 通过产生活性氧激活缺氧诱导因子，并通过促进代谢重编程和炎症诱导肿瘤生长

背景线粒体不仅仅是细胞的动力源；它们决定细胞是死亡还是存活。线粒体是动态的细胞器，会根据环境条件不断进行融合和裂变。我们之前表明，低氧环境（缺氧）中的细胞线粒体过度融合形成扩大或高度互连的网络，具有增强的代谢功效和抗凋亡能力。已经报道了癌症中线粒体外观和代谢能力的改变。然而，调节癌症中线粒体动力学和代谢的精确机制尚不清楚。由于缺氧在这些异常线粒体的产生中起作用，我们质疑它是否调节线粒体功能。线粒体外膜电压​​依赖性阴离子通道 1 (VDAC1) 处于调节代谢和细胞凋亡的中心阶段。我们之前证明 VDAC1 不仅在各种缺氧癌细胞中而且在肺腺癌患者的肿瘤组织中被翻译后 C 端裂解。与常氧癌细胞相比，线粒体扩大和 VDAC1 裂解的细胞对化疗刺激的细胞死亡具有更强的抵抗力。结果 Vdac1 敲除的小鼠胚胎成纤维细胞 (MEF) 的转录组分析不仅突出了癌症和炎症通路的改变，而且还突出了常氧中的缺氧诱导因子-1 (HIF-1) 信号通路。由于活性氧 (ROS) 的积累，HIF-1α 在常氧条件下稳定，减少呼吸和糖酵解并维持基础细胞凋亡。然而，在缺氧条件下，细胞外信号调节激酶 (ERK) 的激活与呼吸的维持和糖酵解的增加相结合，抵消了增强 ROS 的有害影响，从而使 Vdac1−/− MEF 在缺氧条件下比野生型 MEF 增殖得更好。RAS 转化的 Vdac1-/- MEF 的同种异体移植物表现出 HIF-1α 和 HIF-2α 的稳定性、血管不稳定和强烈的炎症反应。此外，HIF-1 靶标和肿瘤抑制基因 Cdkn2a 的表达显着降低。因此，RAS 转化的 Vdac1-/- MEF 肿瘤比野生型 MEF 肿瘤生长得更快。结论癌细胞中的代谢重编程可能受 VDAC1 通过血管不稳定和炎症的调节。