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. 2019 Mar 15;663:109-119.
doi: 10.1016/ Epub 2019 Jan 8.

Mitochondrial Regulation of Airway Smooth Muscle Functions in Health and Pulmonary Diseases

Free PMC article

Mitochondrial Regulation of Airway Smooth Muscle Functions in Health and Pulmonary Diseases

Shi Pan et al. Arch Biochem Biophys. .
Free PMC article


Mitochondria are important for airway smooth muscle physiology due to their diverse yet interconnected roles in calcium handling, redox regulation, and cellular bioenergetics. Increasing evidence indicates that mitochondria dysfunction is intimately associated with airway diseases such as asthma, IPF and COPD. In these pathological conditions, increased mitochondrial ROS, altered bioenergetics profiles, and calcium mishandling contribute collectively to changes in cellular signaling, gene expression, and ultimately changes in airway smooth muscle contractile/proliferative properties. Therefore, understanding the basic features of airway smooth muscle mitochondria and their functional contribution to airway biology and pathology are key to developing novel therapeutics for airway diseases. This review summarizes the recent findings of airway smooth muscle mitochondria focusing on calcium homeostasis and redox regulation, two key determinants of physiological and pathological functions of airway smooth muscle.

Keywords: Airway smooth muscle; Calcium; Contraction; Mitochondria; Proliferation.


Figure 1:
Figure 1:. Oxidative phosphorylation.
Mitochondria are responsible for energy production through the process of cellular respiration. The reduction of each complex in the electron transport chain allows for protons to be pumped into the intermembrane space. The buildup of protons in its space eventually creates a concentration gradient known as the proton motive force. The influx of protons back into the mitochondrial matrix through the proton pump, F1F0 ATP synthase, drives the conversion of ADP and inorganic phosphate into ATP, which is an important source of energy for smooth muscle contraction. Activation of multiple mitochondrial enzymes is dependent upon calcium concentration in the mitochondria. Uptake of calcium from cytosol into mitochondrial matrix positively regulate ATP synthesis.
Figure 2:
Figure 2:. G-protein mediated Ca2+ mobilization.
ASM contraction and relaxation are dependent on changes in cytosolic and mitochondrial calcium. GPCR stimulation and subsequent G protein activation leads to the activation of PLC-β. PIP2 is cleaved by PLC-β into IP3 and DAG. IP3 binds to IP3-gated Ca2+ channels on the SERCA membrane, causing these channels to open and allow Ca2+ to be released into the cytosol. Mitochondria which are in close proximity to the SR are able to uptake Ca2+ through the MCU, where it can be used by calcium-dependent dehydrogenases in the TCA cycle. Transient mitochondrial calcium fluxes thus lead to the increases in ATP production necessary for both temporary and prolonged ASM contraction.
Figure 3:
Figure 3:. Role of ROS/RNS in mitochondrial dysfunction.
ASM contraction and relaxation are dependent on changes in cytosolic and mitochondrial calcium. Uncoupling of mitochondria from the ER/SR membrane leads to reduced mitochondrial Ca2+ flux, stress-related increases in ROS/RNS and reduced degradation of ROS. Increased ROS/RNS act as a second messenger or chemically modulate the functional ability of ASM proteins and results in increased airway inflammation, airway hyperresponsiveness (AHR) and ASM remodeling.
Figure 4:
Figure 4:. Hypoxia and airway smooth muscle remodeling.
Under non-hypoxic conditions, HIF-1α is bound in a complex with VHL and Elo, hydroxylated at two proline residues and targeted for proteasomal degradation via E3 ligase-mediated ubiquitinylation. However, chronically inflamed lung tissue is susceptible to oxygen deprivation due to thickening of the basement membrane. Hypoxia allows unbound HIF-1α to form a heterodimer with HIF-β, translocate into the nucleus and binds to hypoxia response elements. Upregulation of these response elements plays a major role in angiogenesis in the extracellular matrix of asthmatic lung tissue.

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