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

Stephen L. Archer, Mardi Gomberg-Maitland, Michael L. Maitland, Stuart Rich, Joe G.N. Garcia, E. Kenneth Weir

Research output: Contribution to journalReview articlepeer-review

260 Scopus citations

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 O2-sensitive K+ channel (Kv1.5), transcription factor activation [hypoxia-inducible factor-1α (HIF-1α) 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-1α-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-1α activation. Three newly recognized mitochondrial abnormalities disrupt the mitochondria-ROS-HIF-1α-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-1α-Kv1.5 O2-sensing pathway contribute to the pathogenesis of PAH and cancer and constitute promising therapeutic targets.

Original languageEnglish (US)
Pages (from-to)H570-H578
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume294
Issue number2
DOIs
StatePublished - Feb 2008

Keywords

  • Fawn-hooded rats
  • Hypoxia-inducible factor-1α
  • Lung cancer
  • Mitochondrial electron transport chain
  • Mitochondrial fusion
  • Nuclear factor-activating T cells
  • Pyruvate dehydrogenase kinase
  • Reactive oxygen species
  • Voltage-gated potassium channels

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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