title: 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 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.
authors.affiliation: University of Rochester Medical Center, 601 Elmwood Ave., Box 711, Rochester, NY 14642, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Brookes
authors.forename: Yisang
authors.initials: Y
authors.lastname: Yoon
authors.forename: James L
authors.initials: JL
authors.lastname: Robotham
authors.forename: M W
authors.initials: MW
authors.lastname: Anders
authors.forename: Shey-Shing
authors.initials: SS
authors.lastname: Sheu
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology*; D002118:Calcium / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology*; D007473:Ion Channels / Q000502:physiology; D008928:Mitochondria / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D007473:Ion Channels; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D002118:Calcium