Nobiletin is an 0-methylated flavonoid found in citrus peels that have anticancer, antiviral, neuroprotective; anti-inflammatory activities and depending on the cell types exhibits both pro- or anti-apoptotic properties We have found that nobiletin decreases oxygen consumption by bovine brain isolated mitochondria in the presence of glutamate and malate and increases in the presence of succinate. In paralleli nobiletin increases NADH: oxidation, a-ketoghitarate dehydrogenase activities and through matrix substrate-level phosphorylation elevates the a-ketoglutarate-dependent-production-of ATP. In addition, nobiletin reduces the production of peroxides in the presence of complex I substrates and slightly enhances succinate-driven H(2)0(2) formation. Besides, nobiletin induces transient elevation of membrane potential followed by mild depolarization. Affinity purified, nobiletin binding proteins revealed one major anti-NDUFVl positive protein with 52kD and NADH: ubiquinone oxidoreductase activity. This fraction can produce peroxide that is inhibited by nobiletin. We propose that nobiletin may act as a mild "uncoupler", which through activation of a-ketoglutarate dehydrogenase (a-KGDH)-complex and acceleration of matrix substrate-level phosphorylation maintains membrane potential at an abnormal level. This switch in mitochondrial metabolism could elevate succinate-driven oxygen consumption that may underlay in both pro- and anti-apoptotic effects of nobiletin.