Mitochondrial metabolism-mediated redox regulation in cancer progression

Abstract

Cancer cells display abnormal metabolic activity as a result of activated oncogenes and loss of tumor suppressor genes. The Warburg Effect is a common metabolic feature of cancer that involves a preference for aerobic glycolysis over oxidative phosphorylation to generate ATP and building blocks for biosynthesis. However, emerging evidence indicates that mitochondrial metabolic pathways are also reprogrammed in cancer and play vital roles in bioenergetics, biosynthesis, and managing redox homeostasis. The mitochondria act a central hub for metabolic pathways that generate ATP and building blocks for lipid, nucleic acid and protein biosynthesis. However, mitochondrial respiration is also a leading source of reactive oxygen species that can damage cellular organelles and trigger cell death if levels become too high. In general, cancer cells are reported to have higher levels of reactive oxygen species than their non-cancerous cells of origin, and therefore must employ diverse metabolic strategies to prevent oxidative stress. However, mounting evidence indicates that the metabolic profiles between proliferative and disseminated cancer cells are not the same. In this review, we will examine mitochondrial metabolic pathways, such as glutaminolysis, that proliferative and disseminated cancer cells utilize to control their redox status.

Keywords: Cancer progression; Glutaminolysis; Mitochondria metabolism; Redox homeostasis.

Fig. 1

Glutaminolysis promotes ROS detoxification and redox homeostasis in cancer through TCA cycle intermediates. Upregulated GDH1 and other enzymes involved in glutaminolysis maintain increased levels of ⍺-KG and downstream TCA metabolites such as fumarate and malate. Fumarate modulates cysteine residues on Keap-1 to promote antioxidant gene expression through the Nrf-2 transcription factor, and also enhances the antioxidant activity of GPx1. Conversion of malate to oxaloacetate via malate dehydrogenase regenerates NADP + to NADPH, which can directly detoxify mitochondrial ROS or maintain intracellular pools of reduced glutathione.