Cited by 2,575Mitochondrial Function and PathologyCell death mechanisms and regulationAutophagy in Disease and Therapy

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

Brookes, Paul S., Yoon, Yisang, Robotham, James L., Anders, M. W., Sheu, Shey-Shing·2004·American Journal of Physiology-Cell Physiology

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.

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Registry

Crossref · 10.1152/ajpcell.00139.2004

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231 of 231 references verified0 citation errors · 0 not checkable

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  • Peroxides produced by mitochondria can create nonenzymatic shunts in the TCA cycle.

    “Peroxides produced by mitochondria can create nonenzymatic shunts in the TCA cycle (56, 121).”
  • Increased Ca2+ load in the mitochondrial matrix is linked to increased ROS production and permeability transition pore opening, leading to apoptosis.

    “In turn, an increased Ca 2ϩ load in the mitochondrial matrix has been linked to increased ROS production and increased permeability transition pore opening, leading to apoptosis (40,45).”

    From Simvastatin Effects on Skeletal Muscle (2013) · cites this paper as [45]

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Authors
Brookes, P. S., Yoon, Y., Robotham, J. L., Anders, M. W., & Sheu, S.-S.
Affiliations
University of Rochester Medicine (US)
Venue
American Journal of Physiology-Cell Physiology
Published
2004-10
Volume
287
Issue
4
Pages
C817-C833
ISSN
  • 0363-6143 (ISSN-L)
  • 1522-1563
OpenAlex
W2068048197
Cited by
2,575
References
227
Citations by year
2026: 72 · 2025: 112 · 2024: 126 · 2023: 138 · 2022: 144 · 2021: 177 · 2020: 162 · 2019: 134 · 2018: 125 · 2017: 125 · 2016: 122 · 2015: 125 · 2014: 124 · 2013: 129 · 2012: 124
FWCI
5.61
Type
journal article
Language
en
Open access
closed
Locations
  • American Journal of Physiology-Cell Physiology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Medical Center, University of Rochester
  • National Heart, Lung, and Blood Institute (HL 33333, R01HL033333, HL-71158-01, R01HL071158)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK-061991, R01DK061991)
  • National Institute of Neurological Disorders and Stroke (NS-37710, R01NS037710)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
mitochondrial calcium homeostasis, ATP production, reactive oxygen species, mitochondrial dysfunction, mitochondrial permeability transition pore, cytochrome c release, apoptosis, two-hit hypothesis, mitochondrial bioenergetics, calcium signaling
MeSH terms
Adenosine Triphosphate, Calcium, Energy Metabolism, Ion Channels, Mitochondria, Signal Transduction, Reactive Oxygen Species

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