Inflammation-Induced Protein Unfolding in Airway Smooth Muscle Triggers a Homeostatic Response in Mitochondria

Abstract

The effects of airway inflammation on airway smooth muscle (ASM) are mediated by pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFα). In this review article, we will provide a unifying hypothesis for a homeostatic response to airway inflammation that mitigates oxidative stress and thereby provides resilience to ASM. Previous studies have shown that acute exposure to TNFα increases ASM force generation in response to muscarinic stimulation (hyper-reactivity) resulting in increased ATP consumption and increased tension cost. To meet this increased energetic demand, mitochondrial O2 consumption and oxidative phosphorylation increases but at the cost of increased reactive oxygen species (ROS) production (oxidative stress). TNFα-induced oxidative stress results in the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and mitochondria of ASM. In the ER, TNFα selectively phosphorylates inositol-requiring enzyme 1 alpha (pIRE1α) triggering downstream splicing of the transcription factor X-box binding protein 1 (XBP1s); thus, activating the pIRE1α/XBP1s ER stress pathway. Protein unfolding in mitochondria also triggers an unfolded protein response (mtUPR). In our conceptual framework, we hypothesize that activation of these pathways is homeostatically directed towards mitochondrial remodeling via an increase in peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α) expression, which in turn triggers: (1) mitochondrial fragmentation (increased dynamin-related protein-1 (Drp1) and reduced mitofusin-2 (Mfn2) expression) and mitophagy (activation of the Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)/Parkin mitophagy pathway) to improve mitochondrial quality; (2) reduced Mfn2 also results in a disruption of mitochondrial tethering to the ER and reduced mitochondrial Ca2+ influx; and (3) mitochondrial biogenesis and increased mitochondrial volume density. The homeostatic remodeling of mitochondria results in more efficient O2 consumption and oxidative phosphorylation and reduced ROS formation by individual mitochondrion, while still meeting the increased ATP demand. Thus, the energetic load of hyper-reactivity is shared across the mitochondrial pool within ASM cells.

Molecular Mechanisms Underlying TNFα-Induced Mitochondrial Biogenesis in Human Airway Smooth Muscle

“…Thus, TNFα increases metabolic demand, which appears to trigger a homeostatic response to increase ATP production by promoting mitochondrial biogenesis and mitochondrial volume density in hASM cells. In addition, by increasing mitochondrial volume density, the demand for ATP production and oxygen consumption per mitochondrion is reduced, thus limiting reactive oxygen species (ROS)-induced oxidative stress [ 9 , 11 ].…”

“…Airway inflammation is one of the major contributors to the pathophysiology of airway diseases including asthma [ 1 , 2 ], chronic obstructive pulmonary disease (COPD) [ 3 , 4 ], chronic bronchitis [ 5 ], and COVID-19 [ 6 , 7 , 8 ]. Previous studies, including those from our laboratory, have shown that acute exposure to proinflammatory cytokines such as TNFα results in airway smooth muscle (ASM) hyperreactivity in response to agonist stimulation, leading to energetic stress [ 9 , 10 ]. In addition, TNFα induces the proliferation of ASM cells, which also increases energy demand [ 11 ].…”

Mitochondrial Dynamics during Development

“…324,325 • Inflammation: Inflammatory stimuli can promote mitochondrial fragmentation by increased protein unfolding, ER stress, phosphorylation of pro-fission proteins, and decreased respiratory capacity. [326][327][328][329][330] There is also increased oxidative stress; mitochondrial complex III generates superoxide during the ubiquinone (Q)-cycle. 331 Some lesions may show mitochondrial fission, mitophagy, and decreased fusion.…”

Insight into the mitochondrial unfolded protein response and cancer: opportunities and challenges

“…In addition, nicotinamide riboside, a precursor of NAD + , can activate UPR mt , accompanied by a significant increase in the level of UPR mt -related proteins [ 22 , 23 ]. In airway smooth muscle, inflammation-induced accumulation of ROS and overload of damaged proteins activate the UPR mt , and the proinflammatory cytokine TNF-α plays a crucial role in this event [ 24 ]. Moreover, caloric restriction can activate the UPR mt to improve mitochondrial function, and miRNAs are involved as key mediators [ 25 ].…”