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

Paul S. Brookes, Yisang Yoon, James L. Robotham, M. W. Anders, Shey Shing Sheu

Research output: Contribution to journalReview articlepeer-review

1958 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)C817-C833
JournalAmerican Journal of Physiology - Cell Physiology
Issue number4 56-4
StatePublished - Oct 2004
Externally publishedYes


  • Apoptosis
  • Free radicals
  • Ischemia
  • Mitochondria
  • Neurodegeneration
  • Permeability transition
  • Reactive oxygen species

ASJC Scopus subject areas

  • Physiology
  • Cell Biology


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