Both endogenous stimuli, (peroxisomes and mitochondria, along with increased levels of calcium, amyloid-β peptide, α-synuclein, Tau protein, hypoxia, ischemia-reperfusion injury); and exogenous stimuli (pollutants, smoke, xenobiotics, UV radiation) contribute to the activation of APE/REF-1. The gene discussed is APEX1; the disease is ischemia reperfusion injury.