OMA1 reprograms metabolism under hypoxia to promote colorectal cancer development

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. Synopsis Mitochondrial stress sensor OMA1 promotes colorectal cancer development by driving metabolic reprogramming under hypoxia. Therefore, OMA1 may be a potential target for colorectal cancer therapy. OMA1 is upregulated in human colorectal cancer and OMA1 levels correlate with poor survival. Deletion of OMA1 suppresses colorectal cancer development in AOM/DSS and xenograft mouse models. Hypoxia upregulates OMA1 levels. OMA1 is required for HIF-1α stabilization by hypoxia. OMA1 is required for the hypoxia induced increase in glycolytic flux. OMA1 deletion leads to a drop in ROS formation and accumulation of mitochondrial respiratory chain components in mouse colorectal tumors. Graphical Abstract Mitochondrial stress sensor OMA1 promotes colorectal cancer development by driving metabolic reprogramming under hypoxia. Therefore, OMA1 may be a potential target for colorectal cancer therapy.