Submitted on November 12, 2007
Accepted on December 10, 2007
Mitochondrial Metabolism, Redox Signaling and Fusion...a mitochondria-ROS-HIF-1
-Kv1.5 oxygen-sensing pathway intersecting pulmonary hypertension and cancer
Stephen L Archer1*, Mardi Gomberg-Maitland2, Michael L Maitland3, Stuart Rich4, Joe G.N. Garcia5, and E. Kenneth Weir6
1 Cardiology Section, University of Chicago, Chicago, Illinois, United States
2 Medicine/Cardiology, University of Chicago, Chicago, Illinois, United States
3 University of Chicago/Hematology / Oncology, University of Chicago, Chicago, Illinois, United States
4 Medicine, University of Chicago, Chicago, Illinois, United States; Medicine/Cardiology, University of Chicago, Chicago, Illinois, United States
5 Medicine, University of Chicago, Chicago, Illinois, United States
6 MEDICINE, University of Minnesota, MINNEAPOLIS, Minnesota, United States
* To whom correspondence should be addressed. E-mail: sarcher{at}medicine.bsd.uchicago.edu.
Pulmonary arterial hypertension (PAH) is a lethal syndrome characterized by vascular obstruction and right ventricular failure. While the fundamental cause remains elusive, many predisposing and disease-modifying abnormalities occur, including endothelial injury/dysfunction, BMPR-2 gene mutations, decreased expression of the O2-sensitive K+ channel (Kv1.5), transcription factor activation (HIF-1
and NFAT), de novo expression of survivin, and increased expression/activity of both serotonin transporters and platelet-derived growth factor receptors. Together these abnormalities create a cancer-like, proliferative, apoptosis-resistant phenotype in pulmonary artery smooth muscle cells (PASMC). A possible unifying mechanism for PAH comes from studies of fawn-hooded rats, which manifest spontaneous PAH and impaired oxygen sensing. PASMC mitochondria normally produce reactive oxygen 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. Oxygen-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-1α activation. Three newly-recognized mitochondrial abnormalities disrupt the mitochondria-ROS-HIF-1-Kv1.5 pathway: (1)mitochondrial pyruvate dehydrogenase kinase activation (2)SOD2 deficiency (3) fragmentation and/or hyperpolarization of the mitochondrial reticulum. The PDK inhibitor, dichloroacetate, corrects the mitochondrial abnormalities in experimental models of PAH and human cancer, causing regression of both diseases. Mitochondrial abnormalities that disturb the ROS-HIF-1-Kv1.5 oxygen-sensing pathway contribute to the pathogenesis of PAH and cancer and constitute promising therapeutic targets.
