Mechanisms that regulate cell metabolism are a fundamental requirement for cell viability. Normal differentiated cells rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes. In tumor cells, it has historically been assumed that mitochondrial metabolism is significantly diminished, while aerobic glycolysis is enhanced so that it becomes the major ATP source to fuel cancer cell proliferation, a phenomenon known as the Warburg effect. Nevertheless, recent studies have shown that the mitochondrial tricarboxylic acid (TCA) cycle is both functional and essential for tumor growth, because it provides cells with building blocks for the synthesis of macromolecules (proteins, lipids and nucleotides), and reducing equivalents which regulate the redox state of the cell. Therefore, we focus our research on understanding how mitochondrial activity is regulated and how we can modulate it in cancer cells.
We discovered that Ca2+ transfer from the endoplasmic reticulum (ER) to mitochondria, mediated through the inositol trisphosphate receptor channel (InsP3R), maintains normal mitochondrial activity and the absence of this signal generates a bioenergetic crisis that induces selective cancer cell death. We demonstrate that Ca2+ transfer to mitochondria is essential to maintain the activity of pyruvate, α-ketoglutarate and isocitrate dehydrogenases, key rate limiting enzymes of the TCA cycle. In this scenario, we hypothesize that in the absence of Ca2+, tumor cells are unable to use glutamine and the TCA cycle to generate the building blocks needed to proliferate and maintain homeostasis.
We expect that a deeper understanding of the regulation of mitochondria bioenergetics by InsP3R-released Ca2+ will result in the identification of new therapeutic targets.