Key Points
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Warburg observed, 70 years ago, that tumours produce excess lactate in the presence of oxygen. This became known as aerobic glycolysis or the 'Warburg effect' which he interpreted as mitochondrial dysfunction. However, it is now clear that mitochondrial function is essential for cancer cell viability, because elimination of cancer cell mitochondrial DNAs (mtDNAs) reduces their growth rate and tumorigenicity.
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The mitochondrial genome encompasses thousands of copies of the mtDNA and more than one thousand nuclear DNA (nDNA)-encoded genes. mtDNA mutations have been found in various cancers and seem to alter mitochondrial metabolism, enhance tumorigenesis and permit cancer cell adaptation to changing environments.
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Mutations in nDNA genes involved in mitochondrial metabolism, including succinate dehydrogenase (SDH), fumarate hydratase (FH), isocitrate dehydrogenase 1 (IDH1) and IDH2, result in increased succinate, fumarate, or R(-)-2-hydroxyglutarate levels. These metabolic alterations can inhibit various α-ketoglutarate-dependent dioxygenases; they can also activate the NFE2-related factor 2 (NRF2) stress response pathway. All of these effects can contribute to tumorigenesis.
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Activation of signalling pathways and oncogenes that are known to be important in tumorigenesis also affect mitochondrial function. The PI3K–PTEN–AKT pathway shifts metabolism from oxidative to glycolytic, thus permitting the redistribution of glycolytic nutrients from catabolism to anabolism. Activation of MYC induces glutaminolysis, which provides anaplerotic substrates to the mitochondrial tricarboxylic acid cycle, thus enhancing citrate production and its export to the cytosol to provide acetyl-CoA for lipid biogenesis and protein modifications.
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Altered mitochondrial metabolism can increase the production of mitochondrial reactive oxygen species (ROS) and change the cellular redox status, thus altering the activities of transcription factors such as HIF1α and FOS–JUN to change gene expression and stimulate cancer cell proliferation.
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A decrease of the mitochondrial membrane potential or mutation of the promyelocytic leukaemia (PML) gene reduces mitochondrial Ca2+ uptake, thus decreasing the activation of the mitochondrial intrinsic apoptosis pathway.
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Reduced mitochondrial Ca2+ retention increases the cytosolic Ca2+ concentration. This activates mitochondrial retrograde signalling through stimulation of calcineurin and IκBβ-dependent NF-κB, activation of enhanceosome-driven transcription and increased metastatic potential.
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Cancer cell ROS production inactivates caveolin 1 in adjacent stromal fibroblasts. This increases mitophagy, reduces mitochondrial function and increases lactate production in these fibroblasts. Secreted stromal cell lactate then fuels cancer cell oxidative metabolism, which drives tumour growth and proliferation. This is known as the 'reverse Warburg effect'.
Abstract
Contrary to conventional wisdom, functional mitochondria are essential for the cancer cell. Although mutations in mitochondrial genes are common in cancer cells, they do not inactivate mitochondrial energy metabolism but rather alter the mitochondrial bioenergetic and biosynthetic state. These states communicate with the nucleus through mitochondrial 'retrograde signalling' to modulate signal transduction pathways, transcriptional circuits and chromatin structure to meet the perceived mitochondrial and nuclear requirements of the cancer cell. Cancer cells then reprogramme adjacent stromal cells to optimize the cancer cell environment. These alterations activate out-of-context programmes that are important in development, stress response, wound healing and nutritional status.
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Acknowledgements
The author would like to thank L. Adang and M. Lott for their assistance in preparing this manuscript. This work was supported by the US National Institutes of Health (NIH) grants NS21328, NS070298, AG24373 and DK73691, and a Simons Foundation Grant 205844.
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Wallace, D. Mitochondria and cancer. Nat Rev Cancer 12, 685–698 (2012). https://doi.org/10.1038/nrc3365
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DOI: https://doi.org/10.1038/nrc3365
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