title: Acidosis Drives the Reprogramming of Fatty Acid Metabolism in Cancer Cells through Changes in Mitochondrial and Histone Acetylation.
abstract: Bioenergetic preferences of cancer cells foster tumor acidosis that in turn leads to dramatic reduction in glycolysis and glucose-derived acetyl-coenzyme A (acetyl-CoA). Here, we show that the main source of this critical two-carbon intermediate becomes fatty acid (FA) oxidation in acidic pH-adapted cancer cells. FA-derived acetyl-CoA not only fuels the tricarboxylic acid (TCA) cycle and supports tumor cell respiration under acidosis, but also contributes to non-enzymatic mitochondrial protein hyperacetylation, thereby restraining complex I activity and ROS production. Also, while oxidative metabolism of glutamine supports the canonical TCA cycle in acidic conditions, reductive carboxylation of glutamine-derived α-ketoglutarate sustains FA synthesis. Concomitance of FA oxidation and synthesis is enabled upon sirtuin-mediated histone deacetylation and consecutive downregulation of acetyl-CoA carboxylase ACC2 making mitochondrial fatty acyl-CoA degradation compatible with cytosolic lipogenesis. Perturbations of these regulatory processes lead to tumor growth inhibitory effects further identifying FA metabolism as a critical determinant of tumor cell proliferation under acidosis.
authors: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, 53 Avenue Mounier B1.53.09, 1200 Brussels, Belgium.
authors: Cyril
authors: C
authors: Corbet
authors: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, 53 Avenue Mounier B1.53.09, 1200 Brussels, Belgium.
authors: Adán
authors: A
authors: Pinto
authors: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, 53 Avenue Mounier B1.53.09, 1200 Brussels, Belgium.
authors: Ruben
authors: R
authors: Martherus
authors: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, 53 Avenue Mounier B1.53.09, 1200 Brussels, Belgium.
authors: João Pedro
authors: JP
authors: Santiago de Jesus
authors: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, 53 Avenue Mounier B1.53.09, 1200 Brussels, Belgium.
authors: Florence
authors: F
authors: Polet
authors: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, 53 Avenue Mounier B1.53.09, 1200 Brussels, Belgium. Electronic address: olivier.feron@uclouvain.be.
authors: Olivier
authors: O
authors: Feron
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D000107:Acetylation; D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019069:Cell Respiration; D065150:Cellular Reprogramming; D042967:Electron Transport Complex I / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D005973:Glutamine / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053858:Metabolic Networks and Pathways; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D006657:Histones; D017382:Reactive Oxygen Species; D005973:Glutamine; D000105:Acetyl Coenzyme A; D042967:Electron Transport Complex I