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

PS Brookes, Y Yoon, JL Robotham… - … of Physiology-Cell …, 2004 - journals.physiology.org
PS Brookes, Y Yoon, JL Robotham, MW Anders, SS Sheu
American Journal of Physiology-Cell Physiology, 2004journals.physiology.org
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
Ca 2+ homeostasis is now recognized to play a key role in several pathologies. For
example, mitochondrial matrix Ca 2+ overload can lead to enhanced generation of reactive
oxygen species, triggering of the permeability transition pore, and cytochrome c release …
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 Ca 2+ homeostasis is now recognized to play a key role in several pathologies. For example, mitochondrial matrix Ca 2+ 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 Ca 2+ and mitochondrial dysfunction in disease, the molecular mechanisms by which Ca 2+ can elicit mitochondrial dysfunction remain elusive. This review highlights the delicate balance between the positive and negative effects of Ca 2+ 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.
American Physiological Society