Cytokines such as interleukin-6 induce tyrosine and serine phosphorylation of Stat3 that results in activation of Stat3-responsive genes. We provide evidence that Stat3 is present in the mitochondria of cultured cells and primary tissues, including the liver and heart. In Stat3−/− cells, the activities of complexes I and II of the electron transport chain (ETC) were significantly decreased. We identified Stat3 mutants that selectively restored the protein's function as a transcription factor or its functions within the ETC. In mice that do not express Stat3 in the heart, there were also selective defects in the activities of complexes I and II of the ETC. These data indicate that Stat3 is required for optimal function of the ETC, which may allow it to orchestrate responses to cellular homeostasis.

Idiopathic pulmonary arterial hypertension (IPAH) is pathogenetically related to low levels of the vasodilator nitric oxide (NOcellular respiration ͉ nitric oxide ͉ oxygen consumption ͉ pulmonary hypertension ͉ mitochondrion I diopathic pulmonary arterial hypertension (IPAH) is a fatal disease of unknown etiology characterized by a progressive increase in pulmonary artery pressure and vascular growth (1, 2). Secondary forms of pulmonary arterial hypertension (PAH) are associated with known diseases, such as collagen vascular diseases or portal hypertension but in the absence of an identifiable etiology are classified as IPAH. Abnormalities in vasodilators, specifically nitric oxide (NO), have been implicated in the pathogenesis of pulmonary hypertension (1-5). NO is produced in the lung by NO synthases (NOS; EC 1.14.13.39) (6-8). There is conclusive evidence from animal models of pulmonary hypertension, mice genetically deficient in endothelial NOS (eNOS), and complementation studies with gene transfer of NOSs for the concept that NO is a critical determinant of pulmonary vascular tone (6, 7, 9). Furthermore, pulmonary and total body NO are lower in IPAH patients as compared with healthy controls (3,(10)(11)(12), and the decrease of NO has been linked to increased arginase II and decreased eNOS expression in IPAH pulmonary endothelial cells in vivo (10,13).In addition to effects on vascular tone, NO regulates cellular bioenergetics through effects on glycolysis, oxygen consumption by mitochondrion, and mitochondrial biogenesis (14-17). For example, eNOS-deficient mice, which have mild pulmonary hypertension under normoxia and an exaggerated pulmonary vasoconstrictive response to hypoxia (18), have reduced mitochondria content in a wide range of tissues in association with significantly lower oxygen consumption and ATP content (14-17). Mitochondria are essential to cellular energy production in all higher organisms adapted to an oxygen-containing environment, i.e., ATP produced through oxidative phosphorylation. The electrochemical gradient used by mitochondrial F 0 F 1 ATP synthase to synthesize ATP from ADP is generated by the proton pump action performed by Complexes I, III, and IV of the respiratory chain. The proton pumping is accompanied by electron shuttling, whereby Complexes I and II, along with the flavoprotein-ubiquinone oxidoreductase, transfer electrons from different sources to ubiquinone (coenzyme Q). The electrons are then transferred sequentially to Complex III, cytochrome c, Complex IV, and finally to molecular oxygen, the terminal electron acceptor. All multisubunit complexes of the respiratory chain (I-IV) are located in the mitochondrial inner membrane. Thus, mitochondria are the primary oxygen demand in the body, accounting for Ϸ90% of cellular oxygen consumption. Conversely, under limiting oxygen conditions, cells turn to glycolysis to generate energy. In endothelial cells, ATP is generated nearly equivalently by glycolysis and cellular respiration (19), accounting for a relative tolerance ...