Endoplasmic Reticulum-Mitochondria Calcium Communication and the Regulation of Mitochondrial Metabolism in Cancer: A Novel Potential Target

Abstract

Cancer is characterized by an uncontrolled cell proliferation rate even under low nutrient availability, which is sustained by a metabolic reprograming now recognized as a hallmark of cancer. Warburg was the first to establish the relationship between cancer and mitochondria; however, he interpreted enhanced aerobic glycolysis as mitochondrial dysfunction. Today it is accepted that many cancer cell types need fully functional mitochondria to maintain their homeostasis. Calcium (Ca²⁺)-a key regulator of several cellular processes-has proven to be essential for mitochondrial metabolism. Inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca²⁺ transfer from the endoplasmic reticulum to the mitochondria through the mitochondrial calcium uniporter (MCU) proves to be essential for the maintenance of mitochondrial function and cellular energy balance. Both IP3R and MCU are overexpressed in several cancer cell types, and the inhibition of the Ca²⁺ communication between these two organelles causes proliferation arrest, migration decrease, and cell death through mechanisms that are not fully understood. In this review, we summarize and analyze the current findings in this area, emphasizing the critical role of Ca²⁺ and mitochondrial metabolism in cancer and its potential as a novel therapeutic target.

Keywords: AMPK; TCA cycle; inositol triphosphate receptors; mitochondrial Ca2+ uniporter; mitochondrial transport; respiratory chain.

Figure 1

Inositol 1,4,5-trisphosphate receptor (IP3R)-mediated calcium transfer to mitochondria in normal and cancer cells. (A) In normal and cancer cells Ca²⁺ released from the endoplasmic reticulum (ER) through the IP3R enters the mitochondrial matrix through the mitochondrial calcium uniporter (MCU) and activates key dehydrogenases of the tricarboxylic acid (TCA) cycle, maintaining a robust amount of ATP and metabolic intermediates or building blocks for the generation of fatty acids, amino acids and nucleotides allowing the cells to enter the cell cycle, proliferate, and keep normal homeostasis. (B) In normal cells, the inhibition of the Ca²⁺ transfer to mitochondria generates a decrease in TCA cycle activity with the concomitant reduction in ATP and metabolic intermediates, inducing AMPK, autophagy and the complete shutdown of the cell cycle caused in part by a reduction in the availability of nucleotides. (C) In cancer, a similar phenomenon is observed after inhibition of Ca²⁺ transfer to mitochondria; decrease in TCA cycle activity, ATP, and metabolic intermediates, activation of AMPK and autophagy, and reduction in the amount of nucleotides available. However, cancer cells continue entering the cell cycle despite the metabolically unfavorable environment causing cell death (65, 66).