key: cord-0861277-53g7yjf9 authors: Ray, Archita; Jaiswal, Ashish; Dutta, Joytri; Singh, Sabita; Mabalirajan, Ulaganathan title: A looming role of mitochondrial calcium in dictating the lung epithelial integrity and pathophysiology of lung diseases date: 2020-09-21 journal: Mitochondrion DOI: 10.1016/j.mito.2020.09.004 sha: 36c3f69a2c626749e8cd9779a1ef817591bfc467 doc_id: 861277 cord_uid: 53g7yjf9 With the increasing appreciation of mitochondria in modulating cellular homeostasis, various disease biology researchers have started exploring the detailed role of mitochondria in multiple diseases beyond neuronal and muscular diseases. In this context, emerging shreds of evidence in lung biology indicated the meticulous role of lung epithelia in provoking a plethora of lung diseases in contrast to earlier beliefs. As lung epithelia are ceaselessly exposed to the environment, they need to have multiple protective mechanisms to maintain the integrity of lung structure and function. As ciliated airway epithelium and type 2 alveolar epithelia require intense energy for executing their key functions like ciliary beating and surfactant production, it is no surprise that defects in mitochondrial function in these cells could perturb lung homeostasis and engage in the pathophysiology of lung diseases. On one hand, intracellular calcium plays a central role in executing key functions of lung epithelia, and on the other hand maintenance of intracellular calcium needs the buffering role of mitochondria. Thus, the regulation of mitochondrial calcium in lung epithelia seems to be critical in lung homeostasis and could be decisive in the pathogenesis of various lung diseases. Since time immemorial, lung health has been underestimated even though the lung is a 48 vulnerable organ as it has to face numerous environmental irritants. Though air pollution 49 levels touched well beyond the safety limit and have silently killed so many lives hitherto, 50 we didn't make sufficient efforts to reduce air pollution. This is because there is no acute 51 mortality owing to air pollution. As an outcome of this, people across the world have 4 (Carafoli 2010) . However, in a living cell, mitochondrial respiration could be the main 89 inducer for the calcium uptake process. Thus, mitochondrial respiration and its calcium 90 uptake are exclusively interdependent. Earlier functional studies indicated that mitochondria 91 can uptake a large amount of calcium in the presence of phosphate whereas its uptake could 92 be limited in the absence of phosphate (Carafoli 2010 ). Later, a number of proteins had been 93 discovered that regulate the influx and efflux of calcium across mitochondria in both 94 directions (Finkel et al. 2015) . The mitochondrial calcium uniporter (MCU) complex, 95 Na + /Ca 2+ exchanger, and H + /Ca 2+ exchanger are the major proteins that help mitochondrial 96 calcium migrate back and forth (Finkel et al. 2015) . To enter into the mitochondria, 97 cytosolic Ca 2+ has to cross the outer mitochondrial membrane (OMM) and inner swelling and ultimately release of cytochrome c from mitochondria to the cytosol to initiate 122 cellular apoptosis (Sebag et al. 2018) . 123 The cytosolic calcium concentration is tightly regulated in the eukaryotic cell. Calcium 124 ions which play the crucial role of second messenger in the signalling pathways are 125 controlled by various pumps, exchangers, channels and numerous binding proteins. 126 Endoplasmic reticulum (ER) and golgi bodies are the reservoirs of calcium in the cells. The lung homeostasis depends on the elimination of exogenous irritants. In this defence 168 mechanism of safeguarding, the airway epithelium is robust enough to protect the entire lung. The airway epithelium has one effective strategy, mucociliary apparatus, for efficacious 170 protection, and this is based on the trapping of foreign particles inside the "gel" or "viscous" 171 layer followed by continuous upward ciliary beating to propel the foreign particles out of the 172 airway (Ridley and Thornton 2018). It seems that mitochondria have a major role in the 173 effectiveness of mucociliary apparatus in two ways: a) by providing energy for the ciliary 174 beating and b) by less uptake of intracellular calcium into the mitochondria. Among various 175 regulatory mechanisms for ciliary beat frequency, the increase of intracellular calcium is 176 crucial. More importantly, calcium is also important to coordinate the synchronization of 177 ciliary beats of subsequent airway epithelial cells of the larger airway (Schmid and Salathe 178 2011). As increased intracellular calcium is a requisite for the ciliary beat, the reduction in 179 intracellular calcium by mitochondrial uptake theoretically will reduce ciliary beating. This 180 was demonstrated by acetylcholine that has the capacity to inhibit ciliary beating through 181 increased mitochondrial uptake of intracellular calcium. All these indicate the feasible role of 182 mitochondria and mitochondrial calcium towards lung homeostasis. The densely located mitochondria in close proximity to the axoneme basal body of 184 cilia seem to provide energy continuously for the movement of cilia. So cristae was found in the ciliated epithelia of these severe asthmatic patients (Thomas et al. 194 2010). It is well acclaimed that mitochondrial swelling is the end product of mitochondrial 195 calcium overload. Interleukin-13 (IL-13), a pleiotropic Th2 cytokine, is known to promote mitochondrial 239 ROS production, matrix Ca 2+ uptake, and apoptosis in the respiratory epithelium (Sebag et al. The COPD is a debilitating lung condition characterized by airway inflammation (chronic 315 bronchitis), destruction of lung tissue (emphysema) and small airway remodelling (Cloonan 316 and Choi 2016). Although among the COPD patients, 20% are non-smokers, the majority of 317 them have a previous history of cigarette smoking. The status of mitochondria and 318 mitochondrial calcium in the pathogenesis of COPD is extensively investigated. In lung disease biology, most of the currently available therapeutics is based on the earlier 678 conceptual changes (Chu and Drazen 2005) . For example, asthma was considered as a 679 psychosomatic disorder or "asthma nervosa" in Hippocrates period and as a result "mind 680 control" was one of major therapeutic option for asthma in those times. This is partially true 681 now also because neurogenic axis that causes sudden bronchospasm when the asthma patient 682 feels either greatest joy or sad. Later, in 20th century "asthma nervosa" concept was updated 683 with "Airway smooth muscle involvement" followed with "airway hyperresponsiveness" and 684 then with "airway inflammation". 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