OMA1 reprograms metabolism under hypoxia to promote colorectal cancer development

Abstract

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-1a, 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.

Identification and Validation of Hypoxia-Related lncRNA Signature as a Prognostic Model for Hepatocellular Carcinoma

“…Under hypoxia, cancer cells could retain survival and stimulate tumor proliferation, migration, and invasion via glycolysis ( Huang and Zong, 2017 ). Wu et al reported that OMA, an ATP-dependent zinc metalloprotease, promotes cancer development by reprogramming metabolic colorectal cancer under hypoxia ( Wu et al, 2021b ). A recent study revealed that hypoxia downregulates the enzymes of pentose phosphate pathway and upregulates the enzymes of glycolysis in tumor and then stimulate tumor migration while inhibiting tumor proliferation ( Kathagen-Buhmann et al, 2016 ).…”

OMA1 High-throughput Screen Reveals Protease Activation by Kinase Inhibitors

“…For example, cancer survival correlated with OMA1 gene expression levels in multiple studies. 9,58,59 The protooncogene MYC could thereby be responsible for OMA1's differential expression in tumors. 9 Another study placed OMA1 downstream of tumor protein p53.…”

The Role of Mitochondria Dysfunction in Inflammatory Bowel Diseases and Colorectal Cancer

“…On the contrary, OMA1 knockout is known to suppress CRC development. Upon activation by hypoxia, OMA1 increases mitochondrial ROS to stabilize HIF-1α, thus promoting glycolysis and suppressing OXPHOS in CRC cells [ 95 ]. These results suggest the crucial role of OMA1 in HIF-1α-mediated CRC development and a high potential as a target for CRC therapy.…”