1. Academic Validation
  2. OMA1 reprograms metabolism under hypoxia to promote colorectal cancer development

OMA1 reprograms metabolism under hypoxia to promote colorectal cancer development

  • EMBO Rep. 2021 Jan 7;22(1):e50827. doi: 10.15252/embr.202050827.
Zhida Wu 1 Meiling Zuo 1 Ling Zeng 1 Kaisa Cui 2 3 Bing Liu 1 Chaojun Yan 1 Li Chen 1 Jun Dong 1 Fugen Shangguan 4 Wanglai Hu 5 He He 1 Bin Lu 4 Zhiyin Song 1
Affiliations

Affiliations

  • 1 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, Hubei, China.
  • 2 Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China.
  • 3 Laboratory of Cancer Epigenetics, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China.
  • 4 Attardi Institute of Mitochondrial Biomedicine, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 5 School of Basic Medical Science, Anhui Medical University, Hefei, Anhui, China.
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-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.

Keywords

OMA1; colorectal cancer; glycolysis; hypoxia; oxidative phosphorylation.

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