HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/H570    most recent 01324.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Google Scholar Articles by Archer, S. L. Articles by Weir, E. K. PubMed PubMed Citation Articles by Archer, S. L. Articles by Weir, E. K.

INVITED REVIEW

Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1-Kv1.5 O₂-sensing pathway at the intersection of pulmonary hypertension and cancer

¹Department of Medicine, Sections of ²Cardiology and ³Hematology/Oncology, University of Chicago, Chicago, Illinois; and ⁴Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota

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 O₂-sensitive K⁺ channel (Kv1.5), transcription factor activation [hypoxia-inducible factor-1 (HIF-1) 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 O₂ sensing. PASMC mitochondria normally produce reactive O₂ species (ROS) in proportion to PO₂. Superoxide dismutase 2 (SOD2) converts intramitochondrial superoxide to diffusible H₂O₂, which serves as a redox-signaling molecule, regulating pulmonary vascular tone and structure through effects on Kv1.5 and transcription factors. O₂ sensing is mediated by this mitochondria-ROS-HIF-1-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-1 activation. Three newly recognized mitochondrial abnormalities disrupt the mitochondria-ROS-HIF-1-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-1-Kv1.5 O₂-sensing pathway contribute to the pathogenesis of PAH and cancer and constitute promising therapeutic targets.

hypoxia-inducible factor-1; nuclear factor-activating T cells; voltage-gated potassium channels; fawn-hooded rats; mitochondrial fusion; pyruvate dehydrogenase kinase; lung cancer; reactive oxygen species; mitochondrial electron transport chain