Mitochondrial acid-sensing ion channel 1a deficiency induces mitochondrial dysfunction in pulmonary arterial smooth muscle cells.

Authors

Megan N Tuineau, Lindsay M Herbert, Heaven E Medina, Jay S Naik, Thomas C Resta, Nikki L Jernigan

Published in

American journal of physiology. Lung cellular and molecular physiology. Volume 330. Issue 4. Pages L390-L403. Apr 01, 2026. Epub Feb 25, 2026.

Abstract

Pulmonary hypertension (PH) is a progressive vascular disease driven by pulmonary arterial remodeling, characterized by cellular hyperproliferation, resistance to apoptosis, and phenotypic plasticity. Our laboratory has shown that the proton-gated cation channel, acid-sensing ion channel 1a (ASIC1a), is essential for the development of chronic hypoxia (CH)-induced PH in rodents. Importantly, ASIC1a activation occurs without changes in total ASIC1a levels but reflects a hypoxia-dependent redistribution to the plasma membrane in pulmonary arterial smooth muscle cells (PASMCs). In neurons, mitochondrial-localized ASIC1a (mtASIC1a) contributes to oxidative stress-induced mitochondrial membrane potential (ΔΨm) depolarization and apoptosis. Although mtASIC1a has not been described in vascular cells, its role in PASMCs may be relevant to mitochondrial dysfunction and apoptosis resistance in PH. We hypothesize that mtASIC1a is a crucial regulator of PASMC mitochondrial homeostasis, and its loss following CH promotes mitochondrial dysfunction and apoptosis resistance. Consistent with this, mtASIC1a localization was decreased in PASMCs and intrapulmonary arteries from CH rats compared with controls. Functionally, PASMCs from CH rats or Asic1a knockout mice exhibited ΔΨm hyperpolarization, elevated mitochondrial Ca²⁺ and superoxide, impaired mitophagy, and reduced cleaved caspase-3. Transmission electron microscopy revealed mitochondrial morphological changes, including increased size and circularity, decreased aspect ratio, and reduced mitochondrial number per cell, whereas fusion/fission proteins remained largely unchanged. Lentiviral restoration of mtASIC1a prevented ΔΨm hyperpolarization and restored caspase-3 cleavage. These findings identify mtASIC1a as a novel regulator of mitochondrial function in PASMCs, where its loss following CH promotes ΔΨm hyperpolarization, impaired mitophagy, and resistance to apoptosis.NEW & NOTEWORTHY This study identifies mitochondrial acid-sensing ion channel 1a (mtASIC1a) as a novel regulator of mitochondrial homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Critically, mtASIC1a deficiency in PASMCs following in vivo chronic hypoxia or genetic deletion promotes mitochondrial membrane potential (ΔΨm) hyperpolarization, Ca²⁺ and superoxide (O₂^-) accumulation, impaired mitophagy, and caspase inhibition. Restoring mtASIC1a by lentiviral transduction prevents ΔΨm hyperpolarization and restores caspase cleavage, highlighting its importance in mitochondrial signaling and hypoxic pulmonary hypertension pathophysiology.

PMID:
41740252
Bibliographic data and abstract were imported from PubMed on 16 Sep 2026.

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