Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 287, Issue 4, Pages C817-C833Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00139.2004
Keywords
mitochondria; reactive oxygen species; free radicals; apoptosis; neurodegeneration; ischemia; permeability transition
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Funding
- NHLBI NIH HHS [HL-71158-01, HL-33333] Funding Source: Medline
- NIDDK NIH HHS [R01 DK061991, DK-061991] Funding Source: Medline
- NINDS NIH HHS [NS-37710] Funding Source: Medline
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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.
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