Mitochondria and Tumor Metabolic Flexibility: Mechanisms and Therapeutic Perspectives

The pro-proliferative Warburg phenotype of cancer cells, characterized by enhanced aerobic glycolysis and partial suppression of mitochondrial metabolism, is a metabolic adaptation to support continuous cell division. The relative contribution of enhanced glycolysis and oxidative phosphorylation to tumor metabolism and overall adenosine triphosphate (ATP) production is dynamic. Metabolically flexible tumors, switch between predominantly glycolytic and oxidative phenotypes as major contributors to overall cellular metabolism, depending on energetic and biosynthetic demands. Here, we describe cancer metabolism and bioenergetics in relation to tumor heterogeneity and metabolic flexibility, and how novel “metabolic” therapeutic strategies may arrest or slow tumor growth. We also describe novel mitochondrial targets, as well as potential repurposing of drugs to regulate mitochondrial metabolism. Particular emphasis is given to the endogenous and pharmacological regulation of the voltage dependent anion channel (VDAC), that controls the flow of metabolites into mitochondria and the efflux of ATP to the cytosol. Because of its function and location, VDAC operates as a switch to turn-off mitochondrial metabolism and favor glycolysis (pro-Warburg) or to turn-on mitochondrial metabolism and decrease glycolysis (anti-Warburg). A better understanding of mitochondrial metabolism in tumor progression is relevant both for cancer biology and for developing novel pharmacological strategies for cancer treatment.