Calcium and ROS: A mutual interplay

Abstract

Calcium is an important second messenger involved in intra- and extracellular signaling cascades and plays an essential role in cell life and death decisions. The Ca(2+) signaling network works in many different ways to regulate cellular processes that function over a wide dynamic range due to the action of buffers, pumps and exchangers on the plasma membrane as well as in internal stores. Calcium signaling pathways interact with other cellular signaling systems such as reactive oxygen species (ROS). Although initially considered to be potentially detrimental byproducts of aerobic metabolism, it is now clear that ROS generated in sub-toxic levels by different intracellular systems act as signaling molecules involved in various cellular processes including growth and cell death. Increasing evidence suggests a mutual interplay between calcium and ROS signaling systems which seems to have important implications for fine tuning cellular signaling networks. However, dysfunction in either of the systems might affect the other system thus potentiating harmful effects which might contribute to the pathogenesis of various disorders.

Keywords: Calcium; Channels; Endoplasmic reticulum; Mitochondria; NADPH oxidases; Reactive oxygen species.

Graphical abstract

Fig. 1

Membrane transporters of calcium ions localized in the plasma membrane, the endoplasmic reticulum and in mitochondrial membranes. Calcium channels (illustrated by green boxes) transport calcium ions into the cytoplasm upon changes in membrane potential or ligand binding. Calcium pumps (yellow boxes) transport calcium from the cytoplasm or into the endoplasmic reticulum (ER) and are energy-dependent. Sodium–calcium exchangers belong to antiporters transporting calcium ions against sodium ions. Two receptors that are localized in the ER release calcium from the ER store. In mitochondria, calcium transport is realized through the mitochondrial permeability transition pore, mitochondrial uniporter and sodium calcium exchanger. Abbreviations: NCX – sodium-calcium exchanger; VDCC – voltage-dependent calcium channel; PMCA – plasma membrane calcium ATPase; ROC – receptor operated channels; TRPC – transient receptor potential channel; SERCA – sarco/endoplasmic reticulum calcium ATPase; RyR – ryanodine receptor; IP3R – inositol 1,4,5-trisphosphate receptor; mPTP – mitochondrial permeability transition pore; MCU – mitochondrial uniporter.

Fig. 2

Calcium and ROS crosstalk between endoplasmic reticulum and mitochondria. The endoplasmic reticulum (ER) is a major site of calcium storage. Calcium from ER cisternae is flowing mainly through calcium release channels as inositol 1,4,5-trisphosphate receptors (IP₃R) and ryanodine receptors (RyR). These channels are accumulated in mitochondrial associated membranes (MAMs), which associate with the mitochondrial outer membrane. Calcium ions from the cytoplasm enter the mitochondria through voltage dependent anion channels (VDAC) or calcium uniporter. High levels of calcium stimulate respiratory chain activity leading to higher amounts of reactive oxygen species (ROS). ROS can further target ER-based calcium channels leading to increased release of calcium and further increased ROS levels. Increased ROS and calcium load can open the mitochondrial permeability transition pore (mPTP) resulting in the release of pro-apoptotic factors. Abbreviations: SERCA – sarco/endoplasmic reticulum Ca²⁺ ATPase; RyR – ryanodine receptors; IP₃R – IP₃ receptor; VDAC – voltage-dependent anion channel; ANT – adenine-nucleotide transporter; mPTP – mitochondrial permeability transition pore; mNCX – mitochondrial sodium/calcium exchanger.

Fig. 3

ROS and calcium crosstalk can induce ER stress. In the course of oxidative protein folding in the endoplasmic reticulum (ER), reactive oxygen species (ROS) are generated during electron transfer between protein disulfide isomerase (PDI) and endoplasmic reticulum oxidoreductin-1 (ERO1α). PDI can also associate with ROS-generating NADPH oxidases (NOX), further increasing ROS levels in the ER. NOX-derived ROS can modulate SERCA activity thus increasing ER calcium levels, contribute to ER stress and activate the unfolded protein response (UPR). ROS increase calcium release to the mitochondria which activates ROS generation in the mitochondrial respiratory chain. Mitochondrial ROS can affect NOX thus further increasing ROS and calcium load in the ER resulting in a vicious circle ultimately leading to apoptosis. Abbreviations: SERCA – sarco/endoplasmic reticulum Ca²⁺ ATPase; MAM – mitochondria-associated ER membranes; NOX NADPH oxidase; PDI – protein disulfate isomerase; ERO1α – endoplasmic reticulum oxidoreductin-1.