Warburg and Beyond: The Power of Mitochondrial Metabolism to Collaborate or Replace Fermentative Glycolysis in Cancer

Abstract

A defining hallmark of tumor phenotypes is uncontrolled cell proliferation, while fermentative glycolysis has long been considered as one of the major metabolic pathways that allows energy production and provides intermediates for the anabolic growth of cancer cells. Although such a vision has been crucial for the development of clinical imaging modalities, it has become now evident that in contrast to prior beliefs, mitochondria play a key role in tumorigenesis. Recent findings demonstrated that a full genetic disruption of the Warburg effect of aggressive cancers does not suppress but instead reduces tumor growth. Tumor growth then relies exclusively on functional mitochondria. Besides having fundamental bioenergetic functions, mitochondrial metabolism indeed provides appropriate building blocks for tumor anabolism, controls redox balance, and coordinates cell death. Hence, mitochondria represent promising targets for the development of novel anti-cancer agents. Here, after revisiting the long-standing Warburg effect from a historic and dynamic perspective, we review the role of mitochondria in cancer with particular attention to the cancer cell-intrinsic/extrinsic mechanisms through which mitochondria influence all steps of tumorigenesis, and briefly discuss the therapeutic potential of targeting mitochondrial metabolism for cancer therapy.

Keywords: Krebs cycle; Warburg effect; metabolism; mitochondria; oxidative phosphorylation (OXPHOS); therapy; tumor.

Figure 1

Note from the top—glucose to lactic acid—the three enzymatic steps that have been genetically disrupted in our studies by CRISPR-Cas9 (red horizontal triangles). Red dotted arrows represent the Hypoxia Inducible Factors (HIF)-induced genes that are upregulated during tumor hypoxia including GLUT1, HK, GPI, LDHA, MCT4 and PDK1, thereby allowing tumors to have a sustained fermentative glycolysis capacity. Glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1), which is a novel glutathione-independent ferroptosis suppressor, are also depicted in this scheme; both of them prevent the generation of membrane lipid peroxides.

Figure 2

Key conclusions issued from the analysis of fermentative glycolysis (Warburg effect) in normal tissues and cancers [51].