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

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 Ca^2- plus another pathological stimulus can bring about mitochondrial dysfunction.