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.
Highlights
Mitochondria arose around two billion years ago as the result of a symbiotic interaction between an archaeon ancestor and a α-proteobacterium [1]
Glutamine contributes the bulk of carbon to the tricarboxylic acid (TCA) cycle through a phenomenon known as anaplerosis [13], maintaining a robust amount of citrate and malate for biosynthesis of lipids and nucleotides, respectively, in addition to providing an extra supply of reductive power (NADH) [9, 14]
We find that breast and prostate cancer derivate cells, as well as transformed primary fibroblasts, similar to normal cells need constitutive transfer of IP3R released Ca2+ to the mitochondria to maintain the optimal activity of pyruvate dehydrogenase (PDH) and, sufficient amounts of NADH to support the TCA cycle (Figure 1A)
Summary
Mitochondria arose around two billion years ago as the result of a symbiotic interaction between an archaeon ancestor and a α-proteobacterium [1]. Mitochondria play a vital role in metal ion homeostasis [5], programmed cell death [6,7,8], and the synthesis of building blocks for. Calcium and Mitochondria in Cancer the generation of amino acids, lipids, and nucleotides [9]. Glutamine contributes the bulk of carbon to the tricarboxylic acid (TCA) cycle through a phenomenon known as anaplerosis [13], maintaining a robust amount of citrate and malate for biosynthesis of lipids and nucleotides, respectively, in addition to providing an extra supply of reductive power (NADH) [9, 14]. Mitochondria play a pivotal role in maintaining cellular homeostasis, and their function is essential for the viability of cancer cells
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