由于线粒体氧化磷酸化（OXPHOS）的不可逆缺陷，许多癌细胞维持着增强的有氧糖酵解。这种被称为沃堡效应（Warburg effect）的现象最近受到挑战，因为大多数癌细胞都保持OXPHOS。然而，癌细胞是如何协调糖酵解和氧磷的，目前还不清楚。本研究，我们证明OMA1是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。
图 线粒体应激传感器OMA1通过在缺氧条件下驱动代谢重编程来促进结直肠癌的发展。
因此，OMA1可能是大肠癌治疗的潜在靶点
OMA1基因敲除抑制AOM/DSS和异种移植小鼠结直肠癌的发生。
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的糖酵解。
另一方面，在缺氧条件下，OMA1缺失促进NDUFB5、NDUFB6、NDUFA4和COX4L1的积累，支持OMA1抑制结直肠癌中的OXPHOS。
因此，我们的研究结果支持OMA1在糖酵解和OXPHOS的协同作用，以促进结直肠癌的发展，并强调OMA1是结直肠癌治疗的潜在靶点。
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.
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.
原文地址：
https://www.embopress.org/doi/abs/10.15252/embr.202050827?af=R
文章原创；转载请注明来源。
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