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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.
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“Peroxides produced by mitochondria can create nonenzymatic shunts in the TCA cycle (56, 121).”
From Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function (2009) · cites this paper as [56]
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“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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Metadata
- 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
- Publisher
- American Physiological Society
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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