Zn2+ Induces Permeability Transition Pore Opening and Release of Pro-apoptotic Peptides from Neuronal Mitochondria
Open accessAbstract
Rapid entry of Ca(2+) or Zn(2+) kills neurons. Mitochondria are major sites of Ca(2+)-dependent toxicity. This study examines Zn(2+)-initiated mitochondrial cell death signaling. 10 nm Zn(2+) induced acute swelling of isolated mitochondria, which was much greater than that induced by higher Ca(2+) levels. Zn(2+) entry into mitochondria was dependent upon the Ca(2+) uniporter, and the consequent swelling resulted from opening of the mitochondrial permeability transition pore. Confocal imaging of intact neurons revealed entry of Zn(2+) (with Ca(2+)) to cause pronounced mitochondrial swelling, which was far greater than that induced by Ca(2+) entry alone. Further experiments compared the abilities of Zn(2+) and Ca(2+) to induce mitochondrial release of cytochrome c (Cyt-c) or apoptosis-inducing factor. In isolated mitochondria, 10 nm Zn(2+) exposures induced Cyt-c release. Induction of Zn(2+) entry into cortical neurons resulted in distinct increases in cytosolic Cyt-c immunolabeling and in cytosolic and nuclear apoptosis-inducing factor labeling within 60 min. In comparison, higher absolute [Ca(2+)](i) rises were less effective in inducing release of these factors. Addition of the mitochondrial permeability transition pore inhibitors cyclosporin A and bongkrekic acid decreased Zn(2+)-dependent release of the factors and attenuated neuronal cell death as assessed by trypan blue staining 5-6 h after the exposures.
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At equivalent concentrations, zinc causes a larger increase in cytochrome c and AIF than calcium.
“At equivalent concentrations, zinc induces a larger increase in cytochrome c and AIF than Ca 2+ [115].”
From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [115]
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- Authors
- Jiang, D., Sullivan, P. G., Sensi, S. L., Steward, O., & Weiss, J. H.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- Weiss, John H.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-12
- Volume
- 276
- Issue
- 50
- Pages
- 47524-47529
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2057520074
- Cited by
- 265
- References
- 34
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 4 · 2021: 11 · 2020: 11 · 2019: 11 · 2018: 11 · 2017: 9 · 2016: 6 · 2015: 14 · 2014: 5 · 2013: 9 · 2012: 19
- FWCI
- 4.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- National Institutes of Health (5k02ag000836-05, 5r01ns032280-07, 5r01ns030884-11, NS30884)
- National Institute on Aging (AG00836, AG 00919, 2T32 AG 00096, T32AG000096)
- National Institute of Neurological Disorders and Stroke (NS 30884, NS-32280)
- 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 › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- zinc, mitochondrial permeability transition pore, mitochondrial swelling, cytochrome c release, apoptosis-inducing factor, neuronal cell death, calcium uniporter, cyclosporine, bongkrekic acid, cortical neurons
- MeSH terms
- Animals, Anti-Bacterial Agents, Bongkrekic Acid, Brain, Calcium, Cations, Cytochrome c Group, Cytoplasm, Cytosol, Dose-Response Relationship, Drug, Enzyme Inhibitors, Flavoproteins, Humans, Immunohistochemistry, Male, Membrane Proteins, Mitochondria, Necrosis, Neurons, Time Factors, Trypan Blue, Zinc, Cyclosporine, Rats, Sprague-Dawley, Apoptosis, Microscopy, Confocal, Apoptosis Inducing Factor, Rats
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