Targeting 2-oxoglutarate dehydrogenase for cancer treatment.
Ling‐Chu Changa, Shih-Kai Chiangb, Shuen‐Ei Chenb c d e, Mien‐Chie Hunga f g h
- aCenter for Molecular Medicine, China Medical University Hospital, China Medical University Taichung 404, Taiwan
- bDepartment of Animal Science, National Chung Hsing University Taichung 40227, Taiwan
- cThe iEGG and Animal Biotechnology Center, National Chung Hsing University Taichung 40227, Taiwan
- dInnovation and Development Center of Sustainable Agriculture (IDCSA), National Chung Hsing University Taiwan
- eResearch Center for Sustainable Energy and Nanotechnology, National Chung Hsing University Taichung 40227, Taiwan
- fGraduate Institute of Biomedical Sciences, China Medical University Taichung 404, Taiwan
- gDeparment of Biotechnology, Asia University Taichung 413, Taiwan
- hResearch Center for Cancer Biology, China Medical University Taichung 404, Taiwan
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Abstract
Tricarboxylic acid (TCA) cycle, also called Krebs cycle or citric acid cycle, is an amphoteric pathway, contributing to catabolic degradation and anaplerotic reactions to supply precursors for macromolecule biosynthesis. Oxoglutarate dehydrogenase complex (OGDHc, also called α-ketoglutarate dehydrogenase) a highly regulated enzyme in TCA cycle, converts α-ketoglutarate (αKG) to succinyl-Coenzyme A in accompany with NADH generation for ATP generation through oxidative phosphorylation. The step collaborates with glutaminolysis at an intersectional point to govern αKG levels for energy production, nucleotide and amino acid syntheses, and the resources for macromolecule synthesis in cancer cells with rapid proliferation. Despite being a flavoenzyme susceptible to electron leakage contributing to mitochondrial reactive oxygen species (ROS) production, OGDHc is highly sensitive to peroxides such as HNE (4-hydroxy-2-nonenal) and moreover, its activity mediates the activation of several antioxidant pathways. The characteristics endow OGDHc as a critical redox sensor in mitochondria. Accumulating evidences suggest that dysregulation of OGDHc impairs cellular redox homeostasis and disturbs substrate fluxes, leading to a buildup of oncometabolites along the pathogenesis and development of cancers. In this review, we describe molecular interactions, regulation of OGDHc expression and activity and its relationships with diseases, specifically focusing on cancers. In the end, we discuss the potential of OGDHs as a therapeutic target for cancer treatment.
TL;DRThe potential of Oxoglutarate dehydrogenase complex (OGDHc) as a therapeutic target for cancer treatment is discussed, with accumulating evidences suggest that dysregulation of OGDHc impairs cellular redox homeostasis and disturbs substrate fluxes, leading to a buildup of oncometabolites along the pathogenesis and development of cancers. (Semantic Scholar)