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Mitochondrial Dysfunction and Allergic Disease
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Kritika Khanna, Anurag Agrawal
Apart from regulating immune responses, mitochondria are also important for maintaining epithelial barrier function. Recent advances highlight the active role of epithelial cells in pathogenesis of allergic disorders. Epithelial cells are the first line of defense as they are the primary barrier between the noxious external agents like pollutants, allergens, cigarette smoke and pathogens, and body’s internal environment. Disruption of the epithelial barrier has been reported in allergic diseases like atopic dermatitis, peanut allergy, pollen allergies and allergic asthma. Compromised epithelial barrier can not only increase the risk of allergen sensitization but also initiate immune responses and signal transduction cascades, altering tissue homeostasis (Mattila et al. 2011). Recent studies show the role of mitochondrial function in maintaining this epithelial integrity. Sebag et al. demonstrated that mitochondrial calcium uniporter (MCU), which resides in the organelle’s inner membrane and regulates Ca2+ uptake in mitochondrial matrix, is critical in regulating epithelial barrier function. Mitochondrial calcium overload leads to accumulation of mtROS, which consequently leads to dissipation of mitochondrial membrane potential and swelling of mitochondria. This, in turn, leads to cytochrome c release and induction of cellular apoptosis. In this study, the authors show that inhibition of MCU in primary human airway epithelial cells decreased IL-13 mediated mitochondrial Ca2+ uptake, abolished mtROS production and preserved mitochondrial membrane potential. It also protected against cytokine induced cellular apoptosis and decreased impairment of barrier function caused by IL-13. These in vitro findings were also confirmed in MCU-/- mice. Upon ovalbumin induced allergic inflammation, MCU deletion decreased apoptosis within large airway epithelial cells and preserved expression of tight junction protein ZO-1, thus maintaining the epithelial barrier integrity (Sebag et al. 2018). Another study highlights the link between mitochondrial homeostasis and epithelial barrier permeability via a phospholipid transfer protein Stard-7. Stard-7 promotes the uptake of phosphatidylcholine (PC) in mitochondria. PC is the major phospholipid species in mitochondria and is important for maintaining mitochondrial function. Knockdown of Stard7 in bronchial epithelial cells and its targeted knockout in lung epithelial cells in mice (Stard7epiΔ/Δ) led to altered mitochondrial structure, along with perturbed mitochondrial respiration, increased mtROS and mtDNA damage. This was also associated with impaired epithelial barrier permeability, both in vitro and in vivo. Interestingly, the reduced levels of tight junction proteins as seen in the Stard7 downregulated epithelial cells were restored upon treatment with mitochondrial targeted antioxidant – Mito TEMPO. Concordantly, paracellular barrier leak in the tracheal epithelial cells isolated from the Stard7epiΔ/Δ mice was also restored upon MitoTEMPO treatment (Yang et al. 2017).
A mechanistic overview of spinal cord injury, oxidative DNA damage repair and neuroprotective therapies
Published in International Journal of Neuroscience, 2023
Jaspreet Kaur, Aditya Mojumdar
Following the injury, due to the combination of various damages discussed earlier, the concentration of extracellular glutamate significantly increases, causing the depolarization of neurons [21]. Glutamate binds to NMDA, AMPA and kainite receptors causing an influx of calcium in neurons, glia, oligodendrocytes, endothelial cells and astrocytes [38, 52–54]. Due to excess intracellular Ca2+, astrocytes release glutamate which is not up-taken due to lipid peroxidation leading to further increase in extracellular glutamate concentration [38]. Prolonged excess of intracellular Ca2+ further damage organelles like mitochondria or endoplasmic reticulum [55–57]. Mitochondrial calcium uniporter facilitates the uptake of Ca2+ into the mitochondria which later promotes apoptosis or necrosis [58,59]. Calcium accumulation induces compromised mitochondrial respiration, disabling Na+/K+ ATPases, and further resulting in an increased concentration of intracellular Na+ [60–62]. Persistent depolarization causes a passive influx of Cl– and water inside the cells leading to osmotic swelling that can contribute to cellular death [63]. Excessive calcium activates various enzymes such as cytosolic proteases like calpain, attacks the cytoskeleton; protein kinases, phosphorylate the proteins and disrupt the cellular functions; lipases, damage the cellular and membrane organelles; and nucleases, affect the chromatin organization by damaging the DNA [38, 64,65].
Role of the mitochondrial calcium uniporter in Mg2+-free-induced epileptic hippocampal neuronal apoptosis
Published in International Journal of Neuroscience, 2020
Yingjiao Li, Cui Wang, Yajun Lian, Haifeng Zhang, Xianghe Meng, Mengyan Yu, Yujuan Li, Nanchang Xie
Disturbance of mitochondrial Ca2+ homeostasis plays a vital role in seizure-induced neuronal damage [1]. The mitochondrial calcium uniporter (MCU) is a selective Ca2+ uniporter located on the mitochondrial inner membrane, which controls the uptake of mitochondrial Ca2+ [2]. Excessive Ca2+ entry into the mitochondrial matrix threatens cell survival by increasing mitochondrial reactive oxygen species (ROS) production, triggering mitochondrial permeability transition pore (mPTP) opening, and releasing pro-apoptotic factors such as cytochrome c, along with the activation of caspase [3, 4]. In our previous study, we found that MCU inhibition exerts neuroprotective effects against seizure-induced neuronal injury in vivo [5]. However, the underlying mechanism has not been completely clarified.
MCUB and mitochondrial calcium uptake – modeling, function, and therapeutic potential
Published in Expert Opinion on Therapeutic Targets, 2020
Jonathan P. Lambert, Emma K. Murray, John W. Elrod
The genetic identification of the mtCU quickly led to the realization of considerable complexity due to its macromolecular nature. The precise stoichiometry and molecular weight (MW) of the uniporter remain unknown, but in general, blue native page and size-exclusion chromatography suggests a complex of ~600–800 kD in size [7,8,]. MCU (Mitochondrial Calcium Uniporter), the pore-forming subunit necessary for Ca2+ permeation, likely predominantly exists as a tetramer in a ‘dimer of dimers’ configuration [9]. The N- and C-terminus face the matrix, with two transmembrane domains forming a hydrophilic channel containing a highly conserved DIME sequence necessary for Ca2+ selectivity. MICU1 and MICU2 (Mitochondrial Calcium Uptake 1/2) contain EF-hand motifs to mediate Ca2+ binding to regulate channel opening. They inhibit channel activity at low cCa2+ concentrations and sense elevations in cytosolic Ca2+ levels to increase open probability (gatekeeping function) [10–12]. EMRE (Essential MCU Regulator) is another mtCU subunit necessary for uniporter function, which is a conduit for the interaction between MCU and MICU1 [13,14,]. MCUB, a gene paralog of the pore-forming subunit, was originally proposed to exert a dominant negative effect on uniporter function [15]. MCUB shares ~50% amino acid sequence identity with MCU and contains an identical DIME sequence shown to be critical for Ca2+ pore selectivity calling into question MCUBs true mechanism of action [15].