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The Role of Mitochondrial Fat Oxidation in Cancer Cell Proliferation and Survival

by 1,2,3 and 1,2,3,*
1
Department of Medicine, Division of Endocrinology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
2
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
3
Molecular Biology Institute at UCLA, Los Angeles, CA 90095, USA
*
Author to whom correspondence should be addressed.
Cells 2020, 9(12), 2600; https://doi.org/10.3390/cells9122600
Received: 3 October 2020 / Revised: 10 November 2020 / Accepted: 2 December 2020 / Published: 4 December 2020
(This article belongs to the Special Issue Regulation of Lipid Metabolism in Health and Disease)
Tumors remodel their metabolism to support anabolic processes needed for replication, as well as to survive nutrient scarcity and oxidative stress imposed by their changing environment. In most healthy tissues, the shift from anabolism to catabolism results in decreased glycolysis and elevated fatty acid oxidation (FAO). This change in the nutrient selected for oxidation is regulated by the glucose-fatty acid cycle, also known as the Randle cycle. Briefly, this cycle consists of a decrease in glycolysis caused by increased mitochondrial FAO in muscle as a result of elevated extracellular fatty acid availability. Closing the cycle, increased glycolysis in response to elevated extracellular glucose availability causes a decrease in mitochondrial FAO. This competition between glycolysis and FAO and its relationship with anabolism and catabolism is conserved in some cancers. Accordingly, decreasing glycolysis to lactate, even by diverting pyruvate to mitochondria, can stop proliferation. Moreover, colorectal cancer cells can effectively shift to FAO to survive both glucose restriction and increases in oxidative stress at the expense of decreasing anabolism. However, a subset of B-cell lymphomas and other cancers require a concurrent increase in mitochondrial FAO and glycolysis to support anabolism and proliferation, thus escaping the competing nature of the Randle cycle. How mitochondria are remodeled in these FAO-dependent lymphomas to preferably oxidize fat, while concurrently sustaining high glycolysis and increasing de novo fatty acid synthesis is unclear. Here, we review studies focusing on the role of mitochondrial FAO and mitochondrial-driven lipid synthesis in cancer proliferation and survival, specifically in colorectal cancer and lymphomas. We conclude that a specific metabolic liability of these FAO-dependent cancers could be a unique remodeling of mitochondrial function that licenses elevated FAO concurrent to high glycolysis and fatty acid synthesis. In addition, blocking this mitochondrial remodeling could selectively stop growth of tumors that shifted to mitochondrial FAO to survive oxidative stress and nutrient scarcity. View Full-Text
Keywords: mitochondria; fatty acid oxidation; glycolysis; lipogenesis; cancer; ISR; ATF4 mitochondria; fatty acid oxidation; glycolysis; lipogenesis; cancer; ISR; ATF4
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MDPI and ACS Style

De Oliveira, M.P.; Liesa, M. The Role of Mitochondrial Fat Oxidation in Cancer Cell Proliferation and Survival. Cells 2020, 9, 2600. https://doi.org/10.3390/cells9122600

AMA Style

De Oliveira MP, Liesa M. The Role of Mitochondrial Fat Oxidation in Cancer Cell Proliferation and Survival. Cells. 2020; 9(12):2600. https://doi.org/10.3390/cells9122600

Chicago/Turabian Style

De Oliveira, Matheus P.; Liesa, Marc. 2020. "The Role of Mitochondrial Fat Oxidation in Cancer Cell Proliferation and Survival" Cells 9, no. 12: 2600. https://doi.org/10.3390/cells9122600

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