Crosstalk between Calcium and ROS in Pathophysiological Conditions

Abstract

Calcium ions are highly versatile intracellular signals that regulate many cellular processes. The key to achieving this pleiotropic role is the spatiotemporal control of calcium concentration evoked by an extensive molecular repertoire of signalling components. Among these, reactive oxygen species (ROS) signalling, together with calcium signalling, plays a crucial role in controlling several physiopathological events. Although initially considered detrimental by-products of aerobic metabolism, it is now widely accepted that ROS, in subtoxic levels, act as signalling molecules. However, dysfunctions in the mechanisms controlling the physiological ROS concentration affect cellular homeostasis, leading to the pathogenesis of various disorders.

Figure 1

Schematic representation of the mitochondrial Ca²⁺ uniporter (MCU) complex. The MCU complex is composed by pore-forming subunits (that comprise the channel subunits MCU, the dominant-negative subunits MCUb, and the transmembrane regulator EMRE) and regulatory subunits (MICU1 and MICU2). MICU1 and MICU2 sense, through EF-hand domains, the increase of Ca²⁺ levels in the intermembrane space (IMS). In resting conditions (on the left), MICU1-MICU2 heterodimers act as gatekeeper of the channel, thus preventing Ca²⁺ vicious cycling and mitochondrial matrix overload. Increases in calcium concentration as a result of cell stimulation (on the right) not only release the inhibitory function of the MICU1-MICU2 heterodimers but also further stimulate MCU channel opening, ensuring the prompt response of mitochondrial metabolism to cell stimulation.

Figure 2

ROS production and scavenging systems. In physiological conditions, the balance between ROS generation and ROS scavenging is highly controlled. The energy production pathways (TCA cycle and OXPHOS), enzymatic reactions, by-products of metabolic pathways, and physical or chemical agents can lead to ROS production. As for the ROS-scavenging mechanisms, enzymatic defences and antioxidant scavengers neutralize the free radical reactions. When an imbalance between ROS production and ROS scavenging occurs, cells undergo oxidative stress, leading to severe cellular damage, cell death, and consequently whole organ and organism failure.

Figure 3

Regulation of mitochondrial Ca²⁺ uptake controls energy metabolism, mtROS production, and cell death. mtROS represent a by-product of oxidative phosphorylation and exert a beneficial or detrimental effect depending on their concentration and on the biological contest. In physiological conditions, mitochondrial Ca²⁺ uptake stimulates the TCA cycle and ATP production (left part). At physiological [Ca²⁺]_mit, the amount of ROS is counteracted by the activity of the antioxidant system (left part). In pathological conditions, excessive Ca²⁺ accumulation by mitochondria (right part) increases mtROS production which, in turn, affects antioxidant response. Altogether, this leads to the increase in the mPTP open probability, leading to irreversible collapse of the mitochondrial membrane potential, swelling of mitochondria, and thus release of cytochrome c, culminating in cell death.