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

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

The Mitochondrial Complex(I)ty of Cancer

Recent evidence highlights that the cancer cell energy requirements vary greatly from normal cells and that cancer cells exhibit different metabolic phenotypes with variable participation of both glycolysis and oxidative phosphorylation. NADH–ubiquinone oxidoreductase (Complex I) is the largest complex of the mitochondrial electron transport chain and contributes about 40% of the proton motive force required for mitochondrial ATP synthesis. In addition, Complex I plays an essential role in biosynthesis and redox control during proliferation, resistance to cell death, and metastasis of cancer cells. Although knowledge about the structure and assembly of Complex I is increasing, information about the role of Complex I subunits in tumorigenesis is scarce and contradictory. Several small molecule inhibitors of Complex I have been described as selective anticancer agents; however, pharmacologic and genetic interventions on Complex I have also shown pro-tumorigenic actions, involving different cellular signaling. Here, we discuss the role of Complex I in tumorigenesis, focusing on the specific participation of Complex I subunits in proliferation and metastasis of cancer cells