Calcium and Reactive Oxygen Species Signaling Interplays in Cardiac Physiology and Pathologies

Abstract

Mitochondria are key players in energy production, critical activity for the smooth functioning of energy-demanding organs such as the muscles, brain, and heart. Therefore, dysregulation or alterations in mitochondrial bioenergetics primarily perturb these organs. Within the cell, mitochondria are the major site of reactive oxygen species (ROS) production through the activity of different enzymes since it is one of the organelles with the major availability of oxygen. ROS can act as signaling molecules in a number of different pathways by modulating calcium (Ca²⁺) signaling. Interactions among ROS and calcium signaling can be considered bidirectional, with ROS regulating cellular Ca²⁺ signaling, whereas Ca²⁺ signaling is essential for ROS production. In particular, we will discuss how alterations in the crosstalk between ROS and Ca²⁺ can lead to mitochondrial bioenergetics dysfunctions and the consequent damage to tissues at high energy demand, such as the heart. Changes in Ca²⁺ can induce mitochondrial alterations associated with reduced ATP production and increased production of ROS. These changes in Ca²⁺ levels and ROS generation completely paralyze cardiac contractility. Thus, ROS can hinder the excitation-contraction coupling, inducing arrhythmias, hypertrophy, apoptosis, or necrosis of cardiac cells. These interplays in the cardiovascular system are the focus of this review.

Keywords: ROS; calcium; cardiomyopathies; drugs; mitochondria; mitochondrial dysfunction.

Figure 1

Calcium and ROS interplay in mitochondria. The close proximity and juxtaposition of the ER to mitochondria facilitate a straight and selective transport of calcium (Ca²⁺). The mitochondria-associated membranes (MAMs) are the site of contact between the endoplasmic reticulum (ER) and mitochondria. Here calcium release channels accumulate, and these channels include the IP3R localized on the ER membrane, the voltage-dependent anion channel 1 (VDAC1) on the outer mitochondrial membrane (OMM), and the cytosolic glucose-regulated chaperone protein 75 (GRP75) that forms a tether between the two organelles. Increased levels of mitochondrial calcium stimulate the activity of the electron transport chain leading to a higher release of reactive oxygen species (ROS). As a vicious circle ROS can hit Ca²⁺ channels localized in the ER membranes and cause a further leak of Ca²⁺ from the ER that leads to increased ROS production in the mitochondria. A pick in the levels of both Ca²⁺ and ROS opens the mitochondrial permeability transition pore (mPTP), allowing the release of cytochrome c that leads to the activation of apoptosis. Abbreviations: ROS reactive oxygen species; Ca²⁺ calcium ion, IP3R IP3 receptor; GRP75 glucose-regulated chaperone protein 75; VDAC voltage-dependent anion channel; MCU mitochondrial calcium uniporter; c cytochrome c; SERCA sarco/endoplasmic reticulum Ca²⁺ ATPase; RyR ryanodine receptors; mPTP—mitochondrial permeability transition pore; I, II, III, VI, V respiratory complex I–V. Created with BioRender.com.