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Reprogramming of Mitochondrial Signalling and Metabolism in Cancer

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One of the well-established general features of cancer is the switch to glycolytic metabolism despite the presence of oxygen, the so-called “Warburg effect”. Many hypotheses have been made to explain this counterintuitive reprogramming, in which ATP production is far from optimal. Aerobic glycolysis is ...

One of the well-established general features of cancer is the switch to glycolytic metabolism despite the presence of oxygen, the so-called “Warburg effect”. Many hypotheses have been made to explain this counterintuitive reprogramming, in which ATP production is far from optimal. Aerobic glycolysis is sustained by increased glucose uptake, as visualized by cancer imaging techniques used in diagnostics, and by expression of specific oncogenes. At least two beneficial outcomes derive from this switch, i.e. adaptation to hypoxia and redirection of glycolytic intermediates to biosynthetic pathways that sustain cell proliferation. As a consequence, targeting aerobic glycolysis has been considered as the preferred way to contrast cancer cell growth. At the same time, the role of mitochondria in cancer progression has been long neglected. However, in the last years renewed interest has arisen on the role of mitochondria in cancer, which appears to be multifaceted. First, mitochondria enzymes, both of the TCA cycle and of the respiratory chain and ATP synthase, are mutated in specific cancers. Second, besides ATP production, stimulation of mitochondria activity leads to the production of metabolites and reactive oxygen species (ROS) which impinge on cancer cell homeostasis. Mitochondrial Ca2+ uptake exerts a pivotal function in the regulation of these signalling pathways in cancer, in addition to the well-known control TCA cycle enzymes activity. Third, the equilibrium between mitochondria biogenesis and mitophagy, which ensures organelle turnover, plays a critical role in cancer metabolism. Finally, signalling pathways from mitochondria to nucleus and backwards have been described, involving transcription factors and peptides that localize to both organelles and that, besides other functions, play a key role in cancer progression.


Keywords: mitochondria, metabolism, cancer, signalling


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