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

Abstract

EK. Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1␣-Kv1.5 O 2-sensing pathway at the intersection of pulmonary hypertension and cancer. Am J Physiol Heart Circ Physiol 294: H570 -H578, 2008. First published December 14, 2007 doi:10.1152/ajpheart.01324.2007.-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 ϩ 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 O 2 sensing. PASMC mitochondria normally produce reactive O 2 species (ROS) in proportion to PO2. Superoxide dismutase 2 (SOD2) converts intramitochondrial superoxide to diffusible H 2O2, 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-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 O 2-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 PULMONARY ARTERIAL HYPERTENSION is a disease of the pulmonary vasculature, which occurs in a rare idiopathic form (sporadic-

Leptin signalling system as a target for pulmonary arterial hypertension therapy

“…Numerous preclinical studies support the beneficial effects of DCA against experimental PH, including in the chronic hypoxia-and monocrotaline-induced PH [28,[43][44][45][46]. DCA is known to target the cellular glycolysis/glucose oxidation ratio and to shift cell metabolism from anaerobic glycolysis to oxidative phosphorylation, via pyruvate dehydrogenase kinase inhibition, leading to HIF-1α degradation [27].…”

Potassium channels in pulmonary arterial hypertension

“…A cancer-like metabolic shift towards a glycolytic metabolism even in the presence of adequate oxygen, also designated the Warburg effect, has been demonstrated as a pathogenic element that can contribute to the development of PAH [52]. Mitochondrial dysfunction, characterised by hyperpolarisation of mitochondrial membrane potential and fragmentation, generates a low ROS environment causing a pseudo-hypoxic state that rapidly stabilises and triggers nuclear translocation of the master transcription regulator of the adaptive response to hypoxia, hypoxia-inducible factor (HIF)-1α [18,53]. The relationship between HIF-1α activation and K V 1.5 expression was investigated in PAH patients and in fawn-hooded rats, which develop spontaneous PAH with ageing [18].…”

Pulmonary Hypertension Is a Probable NO/ONOO−Cycle Disease: A Review

“…Quite a number of studies have reported substantial mitochondrial dysfunction in PAH [264][265][266][267][268][269]. e genetic studies in [266][267][268] strongly suggest that such mitochondrial dysfunction can have a strong, causal role in PAH and one study used mitochondrial inhibitors which showed a complex causal role in PAH [269].…”

“…e genetic studies in [266][267][268] strongly suggest that such mitochondrial dysfunction can have a strong, causal role in PAH and one study used mitochondrial inhibitors which showed a complex causal role in PAH [269]. Four of these studies [264,266,268,269] all suggest mechanisms by which mitochondrial dysfunction may contribute to the symptoms and signs of PAH. However, none of these provide any evidence that agents that improve mitochondrial function can prevent or produce improvements in PAH.…”