Inflammation-Induced Protein Unfolding in Airway Smooth Muscle Triggers a Homeostatic Response in Mitochondria
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...
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| Format: | Article |
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MDPI AG
2020-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/1/363 |
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| author | Debanjali Dasgupta Philippe Delmotte Gary C. Sieck |
| author_facet | Debanjali Dasgupta Philippe Delmotte Gary C. Sieck |
| author_sort | Debanjali Dasgupta |
| collection | DOAJ |
| description | 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 O<sub>2</sub> 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 (<sup>mt</sup>UPR). 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 Ca<sup>2+</sup> influx; and (3) mitochondrial biogenesis and increased mitochondrial volume density. The homeostatic remodeling of mitochondria results in more efficient O<sub>2</sub> 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. |
| first_indexed | 2024-03-10T13:36:23Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T13:36:23Z |
| publishDate | 2020-12-01 |
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| spelling | doaj.art-fa4e296f43a94775aeac6d37f98342fa2023-11-21T07:31:42ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-12-0122136310.3390/ijms22010363Inflammation-Induced Protein Unfolding in Airway Smooth Muscle Triggers a Homeostatic Response in MitochondriaDebanjali Dasgupta0Philippe Delmotte1Gary C. Sieck2Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USADepartment of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USADepartment of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USAThe 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 O<sub>2</sub> 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 (<sup>mt</sup>UPR). 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 Ca<sup>2+</sup> influx; and (3) mitochondrial biogenesis and increased mitochondrial volume density. The homeostatic remodeling of mitochondria results in more efficient O<sub>2</sub> 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.https://www.mdpi.com/1422-0067/22/1/363reactive oxygen species (ROS)oxidative stressMfn2Drp1MCUasthma |
| spellingShingle | Debanjali Dasgupta Philippe Delmotte Gary C. Sieck Inflammation-Induced Protein Unfolding in Airway Smooth Muscle Triggers a Homeostatic Response in Mitochondria International Journal of Molecular Sciences reactive oxygen species (ROS) oxidative stress Mfn2 Drp1 MCU asthma |
| title | Inflammation-Induced Protein Unfolding in Airway Smooth Muscle Triggers a Homeostatic Response in Mitochondria |
| title_full | Inflammation-Induced Protein Unfolding in Airway Smooth Muscle Triggers a Homeostatic Response in Mitochondria |
| title_fullStr | Inflammation-Induced Protein Unfolding in Airway Smooth Muscle Triggers a Homeostatic Response in Mitochondria |
| title_full_unstemmed | Inflammation-Induced Protein Unfolding in Airway Smooth Muscle Triggers a Homeostatic Response in Mitochondria |
| title_short | Inflammation-Induced Protein Unfolding in Airway Smooth Muscle Triggers a Homeostatic Response in Mitochondria |
| title_sort | inflammation induced protein unfolding in airway smooth muscle triggers a homeostatic response in mitochondria |
| topic | reactive oxygen species (ROS) oxidative stress Mfn2 Drp1 MCU asthma |
| url | https://www.mdpi.com/1422-0067/22/1/363 |
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