Many cancer cells maintain enhanced aerobic glycolysis due to irreversible defective mitochondrial oxidative phosphorylation (OXPHOS). This phenomenon, known as the Warburg effect, is recently challenged because most cancer cells maintain OXPHOS. However, how cancer cells coordinate glycolysis and OXPHOS remains largely unknown. Here, we demonstrate that OMA1, a stress‐activated mitochondrial protease, promotes colorectal cancer development by driving metabolic reprogramming. OMA1 knockout suppresses colorectal cancer development in AOM/DSS and xenograft mice models of colorectal cancer. OMA1‐OPA1 axis is activated by hypoxia, increasing mitochondrial ROS to stabilize HIF‐1α, thereby promoting glycolysis in colorectal cancer cells. On the other hand, under hypoxia, OMA1 depletion promotes accumulation of NDUFB5, NDUFB6, NDUFA4, and COX4L1, supporting that OMA1 suppresses OXPHOS in colorectal cancer. Therefore, our findings support a role for OMA1 in coordination of glycolysis and OXPHOS to promote colorectal cancer development and highlight OMA1 as a potential target for colorectal cancer therapy.

中文翻译：

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OMA1在缺氧下重新编程代谢以促进结直肠癌的发展


许多癌细胞由于不可逆的线粒体氧化磷酸化（OXPHOS）缺陷而维持增强的有氧糖酵解。这种被称为瓦尔堡效应的现象最近受到挑战，因为大多数癌细胞都维持 OXPHOS。然而，癌细胞如何协调糖酵解和 OXPHOS 仍然很大程度上未知。在这里，我们证明 OMA1（一种应激激活的线粒体蛋白酶）通过驱动代谢重编程来促进结直肠癌的发展。 OMA1 敲除可抑制 AOM/DSS 和结直肠癌异种移植小鼠模型中结直肠癌的发展。 OMA1-OPA1轴被缺氧激活，增加线粒体ROS以稳定HIF-1α，从而促进结直肠癌细胞中的糖酵解。另一方面，在缺氧条件下，OMA1 的消耗会促进 NDUFB5、NDUFB6、NDUFA4 和 COX4L1 的积累，支持 OMA1 在结直肠癌中抑制 OXPHOS。因此，我们的研究结果支持 OMA1 在糖酵解和 OXPHOS 协调中的作用，促进结直肠癌的发展，并强调 OMA1 作为结直肠癌治疗的潜在靶点。