# The Role of Mitochondrial Acid-Sensing Ion Channel 1 in Pulmonary Hypertension

> **NIH NIH F31** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2024 · $40,756

## Abstract

PROJECT SUMMARY
 The World Health Organization (WHO) defines five broad groups of pulmonary hypertension (PH),
including PH resulting from chronic lung diseases and/or conditions causing hypoxia (WHO Group III).
Regardless of etiology, central features include increased pulmonary arterial constriction and remodeling.
Unfortunately, current therapies lack pulmonary vasculature specificity and do not address the prominent
pulmonary arterial remodeling; nonetheless, rates of morbidity and mortality for patients with PH remain high.
Our laboratory has identified a pathogenic role of acid-sensing ion channel 1a (ASIC1a) in rodent models of
chronic hypoxia (CH)-induced PH. The prominent role of ASIC1a is independent of changes in gene or protein
expression. Rather, subcellular localization of ASIC1a in PASMC is altered, wherein plasma membrane-localized
ASIC1a (pmASIC1a) is increased and mitochondria-localized ASIC1a (mtASIC1a) is decreased. Following CH,
enhanced activation of pmASIC1a causes increased Na+ and Ca2+ influx, which are associated with pulmonary
arterial smooth muscle cells (PASMC) dysfunction during PH. However, both the physiological role and the effect
of the loss of mtASIC1a on PASMC function are unknown. Our preliminary data shows that the loss of Asic1a
results in mitochondrial membrane potential (ΔΨm) hyperpolarization and decreased caspase activation.
Lentiviral transduction of PASMC from Asic1a knockout mice with mtASIC1a prevents ΔΨm hyperpolarization.
Considering that ΔΨm hyperpolarization is associated with mitochondrial dysfunction and apoptosis resistance,
these data suggest an important role of mtASIC1a for PASMC function.
 Defining the mechanisms of ASIC1a trafficking may provide novel molecular targets to improve PASMC
function during PH. Interestingly, we show that the ASIC1a-binding molecular chaperone, sigma-1 receptor
(σ1R), is upregulated in intrapulmonary arteries following CH. Moreover, we show that the σ1R antagonist,
S1RA, decreases pmASIC1a localization and the σ1R agonist, PRE-084, increases ASIC1a-dependent Ca2+
influx. The proposed studies will test the central hypothesis that σ1R causes altered subcellular localization of
ASIC1a following CH that results in aberrant PASMC function associated with PH. The following aims will be
investigated to test this hypothesis: 1) Determine the contribution of σ1R to the enhanced localization and
activation of pmASIC1a following CH and 2) Define the role of σ1R in mtASIC1a localization and mitochondrial
function. The significance of this research lies in defining the role of σ1R in regulating ASIC1a subcellular
localization, which controls PASMC function. This study also examines the novel role of ASIC1a to regulate
mitochondrial function. These findings address the unmet need for more effective pulmonary hypertension
therapies. Moreover, this training plan will positively impact my technical, analytical, and communication skills
which will propel me to attain a postdocto...

## Key facts

- **NIH application ID:** 10996925
- **Project number:** 1F31HL170503-01A1
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Megan Tuineau
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $40,756
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996925

## Citation

> US National Institutes of Health, RePORTER application 10996925, The Role of Mitochondrial Acid-Sensing Ion Channel 1 in Pulmonary Hypertension (1F31HL170503-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10996925. Licensed CC0.

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