Calcium, ATP, and ROS: a mitochondrial love-hate triangle

Abstract

The mitochondrion is at the core of cellular energy metabolism, being the site of most ATP generation. Calcium is a key regulator of mitochondrial function and acts at several levels within the organelle to stimulate ATP synthesis. However, the dysregulation of mitochondrial Ca2+homeostasis is now recognized to play a key role in several pathologies. For example, mitochondrial matrix Ca2+overload can lead to enhanced generation of reactive oxygen species, triggering of the permeability transition pore, and cytochrome c release, leading to apoptosis. Despite progress regarding the independent roles of both Ca2+and mitochondrial dysfunction in disease, the molecular mechanisms by which Ca2+can elicit mitochondrial dysfunction remain elusive. This review highlights the delicate balance between the positive and negative effects of Ca2+and the signaling events that perturb this balance. Overall, a “two-hit” hypothesis is developed, in which Ca2+plus another pathological stimulus can bring about mitochondrial dysfunction.