Metabolic Reprogramming of Cancer-Associated Fibroblasts by IDH3α Downregulation

Cancer-associated fibroblasts (CAFs) provide critical metabolites for tumor growth and undergo metabolic reprogramming to support glycolysis. However, the molecular mechanisms responsible for this change remain unclear. Here, we report that TGF-beta 1- or PDGF-induced CAFs switch from oxidative phosphorylation to aerobic glycolysis. We identify down-regulation of isocitrate dehydrogenase 3 alpha (IDH3 alpha) as a marker for this switch. Furthermore, miR-424 downregulates IDH3 alpha during CAF formation. Downregulation of IDH3 alpha decreases the effective level of alpha-ketoglutarate (alpha-KG) by reducing the ratio of alpha-KG to fumarate and succinate, resulting in PHD2 inhibition and HIF-1 alpha protein stabilization. The accumulation of HIF-1 alpha, in turn, promotes glycolysis by increasing the uptake of glucose, upregulating expression of glycolytic enzymes under normoxic conditions, and inhibiting oxidative phosphorylation by upregulating NDUFA4L2. CAFs from tumor samples exhibit low levels of IDH3 alpha, and overexpression of IDH3 alpha prevents transformation of fibroblasts into CAFs. Our studies reveal IDH3 alpha to be a critical metabolic switch in CAFs.