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INVITED REVIEW

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

Departments of Anesthesiology, Pharmacology, and Physiology and Mitochondrial Research Interest Group, University of Rochester Medical Center, Rochester New York 14642

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.

mitochondria; reactive oxygen species; free radicals; apoptosis; neurodegeneration; ischemia; permeability transition

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