Cellular and mitochondrial calcium communication in obstructive lung disorders

Abstract

Calcium (Ca²⁺) signalling is well known to dictate cellular functioning and fate. In recent years, the accumulation of Ca²⁺ in the mitochondria has emerged as an important factor in Chronic Respiratory Diseases (CRD) such as Asthma and Chronic Obstructive Pulmonary Disease (COPD). Various reports underline an aberrant increase in the intracellular Ca²⁺, leading to mitochondrial ROS generation, and further activation of the apoptotic pathway in these diseases. Mitochondria contribute to Ca²⁺ buffering which in turn regulates mitochondrial metabolism and ATP production. Disruption of this Ca²⁺ balance leads to impaired cellular processes like apoptosis or necrosis and thus contributes to the pathophysiology of airway diseases. This review highlights the key role of cytoplasmic and mitochondrial Ca²⁺ signalling in regulating CRD, such as asthma and COPD. A better understanding of the dysregulation of mitochondrial Ca²⁺ homeostasis in these diseases could provide cues for the development of advanced therapeutic interventions in these diseases.

Introduction

The lung is a vulnerable organ, susceptible to infections and inhalational injuries from the environment. Chronic Respiratory Diseases (CRD), affecting both the small and large airways, as well as the lung parenchyma are responsible for significant morbidity and mortality across the globe. An estimated 3.8 million deaths occurred due to CRD in the year 2016, accounting for about 9% of the total world mortality (Vos et al., 2017). In the year 2017, 544·9 million people were affected by CRD, marking an increase of 39·8% since 1990 (Soriano et al., 2020). Asthma and Chronic Obstructive Pulmonary Disorder (COPD) are the most common CRDs, contributing to the disease burden significantly. Previous studies show that Ca²⁺ signalling plays a crucial role in the pathophysiology of these diseases. Ca²⁺ is an extremely ubiquitous and versatile cellular messenger, with a dynamic involvement in orchestrating and regulating many cellular functions from survival to death. Two major factors contribute to the expansive nature of Ca²⁺ cascades; its ability to interact with several effectors and its self-regulation.

In the cell, these signalling events are coordinated by a machinery known as the Ca²⁺ toolkit, comprising of various organelles and proteins. The Endoplasmic Reticulum (ER), mitochondria, nucleus and the plasma membrane, along with their channels and transporters, very closely device the relay of Ca²⁺ from the extracellular to intracellular compartments (Contreras et al., 2010, Petersen et al., 2005). While the ER is responsible for storing intracellular Ca²⁺, the mitochondria function as important Ca²⁺ buffers by sensing intracellular Ca²⁺ concentrations and balancing them. (Rizzuto et al., 2012, Walsh et al., 2009). Research in the last few decades has highlighted the dynamic role of mitochondrial Ca²⁺ in mitigating energetics and programmed cell death, both physiologically and pathologically. In this review, we focus on mitochondrial and cytosolic Ca²⁺ signalling in asthma and COPD.