Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction
Open accessAbstract
Oxidative stress is implicated in neuronal apoptosis that occurs in physiological settings and in neurodegenerative disorders. Superoxide anion radical, produced during mitochondrial respiration, is involved in the generation of several potentially damaging reactive oxygen species including peroxynitrite. To examine directly the role of superoxide and peroxynitrite in neuronal apoptosis, we generated neural cell lines and transgenic mice that overexpress human mitochondrial manganese superoxide dismutase (MnSOD). In cultured pheochromocytoma PC6 cells, overexpression of mitochondria-localized MnSOD prevented apoptosis induced by Fe 2+, amyloid β-peptide (Aβ), and nitric oxide-generating agents. Accumulations of peroxynitrite, nitrated proteins, and the membrane lipid peroxidation product 4-hydroxynonenal (HNE) after exposure to the apoptotic insults were markedly attenuated in cells expressing MnSOD. Glutathione peroxidase activity levels were increased in cells overexpressing MnSOD, suggesting a compensatory response to increased H 2 O 2 levels. The peroxynitrite scavenger uric acid and the antioxidants propyl gallate and glutathione prevented apoptosis induced by each apoptotic insult, suggesting central roles for peroxynitrite and membrane lipid peroxidation in oxidative stress-induced apoptosis. Apoptotic insults decreased mitochondrial transmembrane potential and energy charge in control cells but not in cells overexpressing MnSOD, and cyclosporin A and caspase inhibitors protected cells against apoptosis, demonstrating roles for mitochondrial alterations and caspase activation in the apoptotic process. Membrane lipid peroxidation, protein nitration, and neuronal death after focal cerebral ischemia were significantly reduced in transgenic mice overexpressing human MnSOD. The data suggest that mitochondrial superoxide accumulation and consequent peroxynitrite production and mitochondrial dysfunction play pivotal roles in neuronal apoptosis induced by diverse insults in cell culture and in vivo.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Aβ induces production of superoxide (O2·-), nitric oxide (NO·), and multiple reactive species downstream of these radicals in many cells, including cortical neurons.
“Aβ induces production of O2·- nitric oxide (NO·), and multiple RS downstream of these radicals in many cells, including cortical neurons (Keller et al., 1998; Longo et al., 2000; Keil et al., 2004; Malinski, 2007; Stepanichev et al., 2008; Díaz et al., 2010).”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Keller et al., 1998
The Discussion links Aβ-induced apoptosis to superoxide and resulting peroxynitrite formation, and the results report increased peroxynitrite-related signals after Aβ exposure in PC6 cells (page unavailable in our copy). The paper does not show that Aβ induces nitric oxide production; it treats an NO-generating compound as a separate insult. The cited Aβ experiments also do not establish the claim specifically in cortical neurons or across many cell types. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease.
Yoritaka, A., Hattori, N., Uchida, K., Tanaka, M., Stadtman, E. R., & Mizuno, Y. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.7.2696 · Cited by 981 · see citing works
Weisiger, R. A., & Fridovich, I. (1973) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)43969-0 · Cited by 895 · see citing works
Keller, J. N., Pang, Z., Geddes, J. W., Begley, J. G., Germeyer, A., Waeg, G., & Mattson, M. P. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.69010273.x · Cited by 439 · cited 2× · see citing works
“, 1997b), and mitochondrial ion-transport systems (Kristal et al., 1996; Keller et al., 1997).”
BackgroundSelf-citation
Flagged first, then by citations
Research works printed but not linked: 2
- Schreck R, Albermann K , Baeuerle PA (1991) Nuclear factor B: an oxidative stress-responsive transcription factor of eukaryotic cells (a review). Free Radic Res Commun 17:221-237.
- Springer JE, Azbill RD, Mark RJ, Begley JG, Waeg G, Mattson MP (1997) 4-Hydroxynonenal, a lipid peroxidation product, rapidly accu- mulates following spinal cord injury and inhibits glutamate uptake. J Neurochem 68:2469 -2476.
Cited by
Sorted by citations
Nitric Oxide and Peroxynitrite in Health and Disease
Pacher, P., Beckman, J. S., & Liaudet, L. (2007) · Physiological Reviews · doi:10.1152/physrev.00029.2006 · Cited by 6,390 · see citing works
Inflammation and Alzheimer’s disease
Akiyama, H. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00124-x · Cited by 4,514 · see citing works
Oxidative Stress and Vascular Disease
Madamanchi, N. R., Vendrov, A., & Runge, M. S. (2005) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000150649.39934.13 · Cited by 1,618 · see citing works
Apoptosis in neurodegenerative disorders
Mattson, M. P. (2000) · Nature Reviews Molecular Cell Biology · doi:10.1038/35040009 · Cited by 1,605 · see citing works
Self-citationMitochondria in neuroplasticity and neurological disorders
Mattson, M. P., Gleichmann, M., & Cheng, A. (2008) · Neuron · doi:10.1016/j.neuron.2008.10.010 · Cited by 1,081 · see citing works
Self-citationKruman, I. I., Culmsee, C., Chan, S. L., Kruman, Y., Guo, Z., Penix, L., & Mattson, M. P. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-18-06920.2000 · Cited by 784 · see citing works
Self-citationFree Radical Pathways in CNS Injury
LEWÉN, A., MATZ, P., & CHAN, P. H. (2000) · Journal of Neurotrauma · doi:10.1089/neu.2000.17.871 · Cited by 759 · see citing works
Mattson, M. P. (2007) · Aging Cell · doi:10.1111/j.1474-9726.2007.00275.x · Cited by 751 · see citing works
Self-citationReactive Oxygen Species in the Regulation of Synaptic Plasticity and Memory
Massaad, C. A., & Klann, E. (2011) · Antioxidants & Redox Signaling · doi:10.1089/ars.2010.3208 · Cited by 635 · see citing works
Evidence of increased oxidative damage in subjects with mild cognitive impairment
Keller, J. N., Schmitt, F. A., Scheff, S. W., Ding, Q., Chen, Q., Butterfield, D. A., & Markesbery, W. R. (2005) · Neurology · doi:10.1212/01.wnl.0000156156.13641.ba · Cited by 539 · see citing works
Self-citationYu, Z., Luo, H., Fu, W., & Mattson, M. P. (1999) · Experimental Neurology · doi:10.1006/exnr.1998.7002 · Cited by 438 · see citing works
Self-citationMcManus, M. J., Murphy, M. P., & Franklin, J. L. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.0552-11.2011 · Cited by 432 · see citing works
Cheng, A., Yang, Y., Zhou, Y., Maharana, C., Lu, D., Peng, W., Liu, Y., Wan, R., Marosi, K., Misiak, M., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.10.013 · Cited by 371 · see citing works
Self-citationManganese Superoxide Dismutase: Guardian of the Powerhouse
Holley, A. K., Bakthavatchalu, V., Velez-Roman, J. M., & St. Clair, D. K. (2011) · International Journal of Molecular Sciences · doi:10.3390/ijms12107114 · Cited by 358 · see citing works
Self-citationApoptotic and antiapoptotic mechanisms in stroke
Mattson, M. P., Culmsee, C., & Yu, Z. F. (2000) · Cell and Tissue Research · doi:10.1007/s004419900154 · Cited by 318 · see citing works
Self-citationAntioxidants, Redox Signaling, and Pathophysiology in Schizophrenia: An Integrative View
Yao, J. K., & Keshavan, M. S. (2011) · Antioxidants & Redox Signaling · doi:10.1089/ars.2010.3603 · Cited by 285 · see citing works
On the selectivity of superoxide dismutase mimetics and its importance in pharmacological studies
Muscoli, C., Cuzzocrea, S., Riley, D. P., Zweier, J. L., Thiemermann, C., Wang, Z., & Salvemini, D. (2003) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0705430 · Cited by 271 · see citing works
Anti-apoptotic Role of Telomerase in Pheochromocytoma Cells
Fu, W., Begley, J. G., Killen, M. W., & Mattson, M. P. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.11.7264 · Cited by 248 · see citing works
Self-citationKowluru, R. A., Kowluru, V., Xiong, Y., & Ho, Y.-S. (2006) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2006.01.012 · Cited by 233 · see citing works
Keller, J. N., & Mattson, M. P. (1998) · Reviews in the Neurosciences · doi:10.1515/revneuro.1998.9.2.105 · Cited by 217 · see citing works
Self-citationGuo, Q., Sebastian, L., Sopher, B. L., Miller, M. W., Ware, C. B., Martin, G. M., & Mattson, M. P. (1999) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1999.0721019.x · Cited by 197 · see citing works
Self-citationGuo, Q., Robinson, N., & Mattson, M. P. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.20.12341 · Cited by 196 · see citing works
Self-citationReed, T. T., Pierce, W. M., Markesbery, W. R., & Butterfield, D. A. (2009) · Brain Research · doi:10.1016/j.brainres.2009.04.009 · Cited by 190 · see citing works
Sex differences in mitochondrial (dys)function: Implications for neuroprotection
Demarest, T. G., & McCarthy, M. M. (2015) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-014-9583-7 · Cited by 192 · see citing works
The Catalytic Subunit of Telomerase Protects Neurons Against Amyloid β‐Peptide‐Induced Apoptosis
Zhu, H., Fu, W., & Mattson, M. P. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0750117.x · Cited by 175 · see citing works
Self-citationKrishnamurthy, R. G., Senut, M., Zemke, D., Min, J., Frenkel, M. B., Greenberg, E. J., Yu, S., Ahn, N., Goudreau, J., Kassab, M., et al. (2009) · Journal of Neuroscience Research · doi:10.1002/jnr.22071 · Cited by 155 · see citing works
Manganese Superoxide Dismutase Overexpression Attenuates MPTP Toxicity
Klivenyi, P., St. Clair, D., Wermer, M., Yen, H.-C., Oberley, T., Yang, L., & Beal, M. F. (1998) · Neurobiology of Disease · doi:10.1006/nbdi.1998.0191 · Cited by 142 · see citing works
Self-citationManganese superoxide dismutase: Beyond life and death
Holley, A. K., Dhar, S. K., Xu, Y., & St. Clair, D. K. (2012) · Amino Acids · doi:10.1007/s00726-010-0600-9 · Cited by 122 · see citing works
Self-citationRole of the Immune System in the Pathogenesis, Prevention and Treatment of Alzheimer??s Disease
Blasko, I., & Grubeck-Loebenstein, B. (2003) · Drugs & Aging · doi:10.2165/00002512-200320020-00002 · Cited by 108 · see citing works
De Bilbao, F., Arsenijevic, D., Vallet, P., Hjelle, O. P., Ottersen, O. P., Bouras, C., Raffin, Y., Abou, K., Langhans, W., Collins, S., et al. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02432.x · Cited by 108 · see citing works
Awasthi, H., Tota, S., Hanif, K., Nath, C., & Shukla, R. (2010) · Life Sciences · doi:10.1016/j.lfs.2009.11.007 · Cited by 86 · see citing works
IMAI, H., KOUMURA, T., NAKAJIMA, R., NOMURA, K., & NAKAGAWA, Y. (2003) · Biochemical Journal · doi:10.1042/bj20021342 · Cited by 67 · see citing works
Mehta, S. L., Lin, Y., Chen, W., Yu, F., Cao, L., He, Q., Chan, P. H., & Li, P. A. (2011) · Translational Stroke Research · doi:10.1007/s12975-010-0027-3 · Cited by 36 · see citing works
Onyango, I. G., Ahn, J., Tuttle, J. B., Bennett Jr, J. P., & Swerdlow, R. H. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06871.x · Cited by 25 · see citing works
Krishna, G., Hosamani, R., & Muralidhara (2019) · Central Nervous System Agents in Medicinal Chemistry · doi:10.2174/1871524919666190115125900 · Cited by 16 · see citing works
- Authors
- Keller, J. N., Kindy, M. S., Holtsberg, F. W., St. Clair, D. K., Yen, H.-C., Germeyer, A., Steiner, S. M., Bruce-Keller, A. J., Hutchins, J. B., & Mattson, M. P.
- Affiliations
- University of Mississippi Medical Center (US)
- University of Kentucky (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 1998-01-15
- Volume
- 18
- Issue
- 2
- Pages
- 687-697
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6792529
- OpenAlex
- W2117104323
- Cited by
- 863
- References
- 3
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 6 · 2023: 10 · 2022: 15 · 2021: 7 · 2020: 14 · 2019: 14 · 2018: 12 · 2017: 14 · 2016: 16 · 2015: 26 · 2014: 20 · 2013: 30 · 2012: 24
- FWCI
- 27.54
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Kentucky Spinal Cord and Head Injury Research Trust
- National Institutes of Health
- National Institute on Aging (P01AG005119, AG0 5119)
- National Institute of Neurological Disorders and Stroke (NS29001, R01NS029001, NS 35253, R01NS035253)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- neuronal apoptosis, peroxynitrite, lipid peroxidation, oxidative stress, mitochondrial dysfunction, focal cerebral ischemia, superoxide, protein nitration, 4-hydroxynonenal, glutathione peroxidase, caspase activation, mitochondrial membrane potential, amyloid-beta, nitric oxide, uric acid, propyl gallate, glutathione, neuroprotection
- MeSH terms
- Animals, Cell Line, Brain Ischemia, Cysteine Endopeptidases, Humans, Intracellular Membranes, Membrane Lipids, Mice, Transgenic, Mitochondria, Neurons, Nitrates, Nitric Oxide, Superoxide Dismutase, Tyrosine, Lipid Peroxidation, Apoptosis, Oxidative Stress, Mice
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.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
