Inactivation of the TCA cycle enzyme, fumarate hydratase ( FH), drives a metabolic shift to aerobic glycolysis in FH-deficient kidney tumors and cell lines from patients with hereditary leiomyomatosis renal cell cancer (HLRCC), resulting in decreased levels of AMP-activated kinase (AMPK) and p53 tumor suppressor, and activation of the anabolic factors, acetyl-CoA carboxylase and ribosomal protein S6. Reduced AMPK levels lead to diminished expression of the DMT1 iron transporter, and the resulting cytosolic iron deficiency activates the iron regulatory proteins, IRP1 and IRP2, and increases expression of the hypoxia inducible factor HIF-1α, but not HIF-2α. Silencing of HIF-1α or activation of AMPK diminishes invasive activities, indicating that alterations of HIF-1α and AMPK contribute to the oncogenic growth of FH-deficient cells. Display omitted ► Loss of FH drives a glycolytic shift and reduces AMPK levels in HLRCC tumor cells ► Reduced AMPK levels in FH−/− cells activate ACC and rpS6 and decrease p53 levels ► Reduced AMPK levels in FH−/− cells decrease DMT1 levels and increase IRP activities ► Reduced iron uptake and activation of IRPs increase levels of HIF-1α but not HIF-2α