Loss of the mitochondrial enzyme thioredoxin reductase 2 (Txnrd2) results in an impaired cellular redox balance and reduces tumor growth by as much as 50%. Txnrd2 knockout tumors display a delayed angiogenic switch and a strongly diminished tumor vascularization which could, surprisingly, be attributed to high levels of HIF prolyl hydroxylase-2 (PHD2) protein expression. The moderate, but constantly increased mitochondrial hydrogen peroxide burden in Txnrd2 deficient cells leads to sustained JNK activation which in turn appeared as a potent inducer of PHD2 expression arguing for a ROS-driven auto-regulatory loop which protects cells from prolonged HIF-1a accumulation.