title: Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1alpha-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer.
abstract: Pulmonary arterial hypertension (PAH) is a lethal syndrome characterized by vascular obstruction and right ventricular failure. Although the fundamental cause remains elusive, many predisposing and disease-modifying abnormalities occur, including endothelial injury/dysfunction, bone morphogenetic protein receptor-2 gene mutations, decreased expression of the O(2)-sensitive K(+) channel (Kv1.5), transcription factor activation [hypoxia-inducible factor-1alpha (HIF-1alpha) and nuclear factor-activating T cells], de novo expression of survivin, and increased expression/activity of both serotonin transporters and platelet-derived growth factor receptors. Together, these abnormalities create a cancerlike, proliferative, apoptosis-resistant phenotype in pulmonary artery smooth muscle cells (PASMCs). A possible unifying mechanism for PAH comes from studies of fawn-hooded rats, which manifest spontaneous PAH and impaired O(2) sensing. PASMC mitochondria normally produce reactive O(2) species (ROS) in proportion to P(O2). Superoxide dismutase 2 (SOD2) converts intramitochondrial superoxide to diffusible H(2)O(2), which serves as a redox-signaling molecule, regulating pulmonary vascular tone and structure through effects on Kv1.5 and transcription factors. O(2) sensing is mediated by this mitochondria-ROS-HIF-1alpha-Kv1.5 pathway. In PAH and cancer, mitochondrial metabolism and redox signaling are reversibly disordered, creating a pseudohypoxic redox state characterized by normoxic decreases in ROS, a shift from oxidative to glycolytic metabolism and HIF-1alpha activation. Three newly recognized mitochondrial abnormalities disrupt the mitochondria-ROS-HIF-1alpha-Kv1.5 pathway: 1) mitochondrial pyruvate dehydrogenase kinase activation, 2) SOD2 deficiency, and 3) fragmentation and/or hyperpolarization of the mitochondrial reticulum. The pyruvate dehydrogenase kinase inhibitor, dichloroacetate, corrects the mitochondrial abnormalities in experimental models of PAH and human cancer, causing a regression of both diseases. Mitochondrial abnormalities that disturb the ROS-HIF-1alpha-Kv1.5 O(2)-sensing pathway contribute to the pathogenesis of PAH and cancer and constitute promising therapeutic targets.
authors: University of Chicago, Section of Cardiology, IL 60637, USA. sarcher@medicine.bsd.uchicago.edu
authors: Stephen L
authors: SL
authors: Archer
authors: Mardi
authors: M
authors: Gomberg-Maitland
authors: Michael L
authors: ML
authors: Maitland
authors: Stuart
authors: S
authors: Rich
authors: Joe G N
authors: JG
authors: Garcia
authors: E Kenneth
authors: EK
authors: Weir
mesh_terms: D000818:Animals; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology*; D051666:Kv1.5 Potassium Channel / Q000235:genetics / Q000502:physiology*; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000502:physiology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000502:physiology; D000099156:Superoxide Dismutase 2
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051666:Kv1.5 Potassium Channel; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C497442:HIF1A protein, human