Acidosis Drives the Reprogramming of Fatty Acid Metabolism in Cancer Cells through Changes in Mitochondrial and Histone Acetylation

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. [Display omitted] •Chronic tumor acidosis induces metabolic rewiring toward fatty acid oxidation•Acidosis-induced mitochondrial hyperacetylation restrains complex I activity•Histone deacetylation-mediated ACC2 repression allows FAO and FAS concomitance•Fatty acid metabolism is a promising target to tackle the tumor acidic compartment Like hypoxia, acidosis is nowadays recognized as a hallmark of many tumors. Corbet et al. show that acidic pH profoundly reprograms the metabolism of cancer cells toward fatty acid oxidation. Associated changes in the acetylome further tune this rewiring by clamping mitochondrial complex I activity and downregulating acetyl-CoA carboxylase ACC2.