Interrelation between ROS and Ca²⁺ in aging and age-related diseases

Calcium (Ca²⁺) and reactive oxygen species (ROS) are versatile signaling molecules coordinating physiological and pathophysiological processes. While channels and pumps shuttle Ca²⁺ ions between extracellular space, cytosol and cellular compartments, short-lived and highly reactive ROS are constantly generated by various production sites within the cell. Ca²⁺ controls membrane potential, modulates mitochondrial adenosine triphosphate (ATP) production and affects proteins like calcineurin (CaN) or calmodulin (CaM), which, in turn, have a wide area of action. Overwhelming Ca²⁺ levels within mitochondria efficiently induce and trigger cell death. In contrast, ROS comprise a diverse group of relatively unstable molecules with an odd number of electrons that abstract electrons from other molecules to gain stability. Depending on the type and produced amount, ROS act either as signaling molecules by affecting target proteins or as harmful oxidative stressors by damaging cellular components. Due to their wide range of actions, it is little wonder that Ca²⁺ and ROS signaling pathways overlap and impact one another. Growing evidence suggests a crucial implication of this mutual interplay on the development and enhancement of age-related disorders, including cardiovascular and neurodegenerative diseases as well as cancer.