Mitochondrial Protein Akap1 Deletion Exacerbates Endoplasmic Reticulum Stress in Mice Exposed to Hyperoxia.

Sahebgowda Sidramagowda Patil,Jutaro Fukumoto,Lakshmi Galam,Muling Lin,Richard Lockey,Venkata Ramireddy Narala,Mason Breitzig,Ramani Soundararajan,Narasaiah Kolliputi,Matthew Alleyn,Helena Hernández-Cuervo

doi:10.3389/fphar.2022.762840

Abstract

Acute lung injury (ALI) and its severe manifestation, acute respiratory distress syndrome (ARDS), are treated with high concentrations of supplementary oxygen. However, prolonged exposure to high oxygen concentrations stimulates the production of reactive oxygen species (ROS), which damages the mitochondria and accumulates misfolded proteins in the endoplasmic reticulum (ER). The mitochondrial protein A-kinase anchoring protein 1 (Akap1) is critical for mitochondrial homeostasis. It is known that Akap1 deficiency results in heart damage, neuronal development impairment, and mitochondrial malfunction in preclinical studies. Our laboratory recently revealed that deleting Akap1 increases the severity of hyperoxia-induced ALI in mice. To assess the role of Akap1 deletion in ER stress in lung injury, wild-type and Akap1 −/− mice were exposed to hyperoxia for 48 h. This study indicates that Akap1 −/− mice exposed to hyperoxia undergo ER stress, which is associated with an increased expression of BiP, JNK phosphorylation, eIF2α phosphorylation, ER stress-induced cell death, and autophagy. This work demonstrates that deleting Akap1 results in increased ER stress in the lungs of mice and that hyperoxia exacerbates ER stress-related consequences.

Highlights

The most common treatment for human acute respiratory distress syndrome is supplemental oxygen (Kallet and Matthay, 2013)
Wt and A-kinase anchoring protein 1 (Akap1)−/− mice were exposed to normoxia and hyperoxia as described in earlier studies to investigate the impact of Akap1 deletion on endoplasmic reticulum (ER) stress receptors (Kolliputi and Waxman, 2009b; Kolliputi et al, 2010)
The lung samples were subjected to qRT-PCR analysis in Akap1−/− versus Wt mice under normoxia, and the data show a 1.35, 1.36, and 1.35-fold increase in PERK, IRE1α, and ATF6α, respectively (Figures 1A–C) no significant increase was observed under hyperoxia exposure, suggesting that Akap1−/− may cause slight upregulation of unfolded protein response (UPR) at the transcript level under normoxia

Summary

Introduction

The most common treatment for human acute respiratory distress syndrome is supplemental oxygen (Kallet and Matthay, 2013). Prolonged exposure to high concentrations of supplementary oxygen leads to increased production of reactive oxygen species (ROS). This prolonged exposure induces hyperoxic acute lung injury in rodent models (Galam et al, 2015), leading to death (Kwak et al, 2006; Kallet and Matthay, 2013). This hyperoxia-induced stress (Fukumoto et al, 2013) can cause protein misfolding in the ER and trigger unfolded protein response (UPR) (Gewandter et al, 2009). The rodent hyperoxia model mimics the clinical presentation of ALI by augmenting oxidative stress (Kallet and Matthay, 2013) and exacerbating respiratory failure through ER stress, events for which there are no viable treatments (Gewandter et al, 2009). The mechanistic role of mitochondrial proteins in hyperoxia-induced ALI needs clarification

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Results

Conclusion