The Pathophysiological Role of Mitochondrial Acid-Sensing Ion Channel 1a in Hypoxic Pulmonary Hypertension

Pulmonary hypertension (PH) is characterized by increased pulmonary arterial constriction, pulmonary arterial remodeling, and right ventricular dysfunction. While metabolic and mitochondrial derangements are increasingly recognized as central pathogenic features, the underlying mechanisms and effectors are not yet fully understood. Acid-sensing ion channel 1a (ASIC1a) is a proton-gated cation channel involved in the development of chronic hypoxia (CH)-induced PH. ASIC1a represents a potential candidate involved in metabolic-mitochondrial dysfunction, as metabolic byproducts can act as ligands for ASIC1a. Additionally, ASIC1a has recently been identified as a mitochondrial ion channel involved in neuronal death following oxidative stress. Therefore, we hypothesize that ASIC1a functions both as a sensor of metabolic changes and a regulator of mitochondrial homeostasis. Indeed, we found that (i) plasma membrane ASIC1a is activated by glycolytic extracellular acidification and (ii) ASIC1a is required for mitochondrial function. Together, these dual roles place ASIC1a at the axis of PH pathogenesis.