1-Methyl-4-phenylpyridinium-induced Apoptosis in Cerebellar Granule Neurons Is Mediated by Transferrin Receptor Iron-dependent Depletion of Tetrahydrobiopterin and Neuronal Nitric-oxide Synthase-derived Superoxide
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In this study, we investigated the molecular mechanisms of toxicity of 1-methyl-4-phenylpyridinium (MPP(+)), an ultimate toxic metabolite of a mitochondrial neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, that causes Parkinson-like symptoms in experimental animals and humans. We used rat cerebellar granule neurons as a model cell system for investigating MPP(+) toxicity. Results show that MPP(+) treatment resulted in the generation of reactive oxygen species from inhibition of complex I of the mitochondrial respiratory chain, and inactivation of aconitase. This, in turn, stimulated transferrin receptor (TfR)-dependent iron signaling via activation of the iron-regulatory protein/iron-responsive element interaction. MPP(+) caused a time-dependent depletion of tetrahydrobiopterin (BH(4)) that was mediated by H(2)O(2) and transferrin iron. Depletion of BH(4) decreased the active, dimeric form of neuronal nitric-oxide synthase (nNOS). MPP(+)-mediated "uncoupling" of nNOS decreased *NO and increased superoxide formation. Pretreatment of cells with sepiapterin to promote BH(4) biosynthesis or cell-permeable iron chelator and TfR antibody to prevent iron-catalyzed BH(4) decomposition inhibited MPP(+) cytotoxicity. Preincubation of cerebellar granule neurons with nNOS inhibitor exacerbated MPP(+)-induced iron uptake, BH(4) depletion, proteasomal inactivation, and apoptosis. We conclude that MPP(+)-dependent aconitase inactivation, Tf-iron uptake, and oxidant generation result in the depletion of intracellular BH(4), leading to the uncoupling of nNOS activity. This further exacerbates reactive oxygen species-mediated oxidative damage and apoptosis. Implications of these results in unraveling the molecular mechanisms of neurodegenerative diseases (Parkinson's and Alzheimer's disease) are discussed.
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Knocking down frataxin with siRNA in human culture cells (HeLa and 293 cells) caused a defect in ISC proteins, including aconitase.
“Knocking down frataxin with siRNA in human culture cells (HeLa and 293 cells) caused a defect in ISC proteins, including aconitase (191, 281).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [281]
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- Authors
- Shang, T., Kotamraju, S., Kalivendi, S. V., Hillard, C. J., & Kalyanaraman, B.
- Affiliations
- Medical College of Wisconsin (US)
- Corresponding author
- Kalyanaraman, B.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-04
- Volume
- 279
- Issue
- 18
- Pages
- 19099-19112
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2167264230
- Cited by
- 62
- References
- 69
- Citations by year
- 2023: 1 · 2022: 2 · 2021: 2 · 2019: 2 · 2017: 4 · 2016: 5 · 2015: 3 · 2014: 2 · 2013: 2 · 2012: 2
- FWCI
- 4.71
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL068769, 1P01 HL 68769-01)
- National Institute of Neurological Disorders and Stroke (R01NS039958, NS 39958)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- MPP+, MPP+ toxicity, Parkinson's disease, cerebellar granule cells, apoptosis, transferrin receptor, iron absorption, mitochondrial complex I inhibition, reactive oxygen species, superoxide, sepiapterin, neurodegeneration
- MeSH terms
- Aconitate Hydratase, Animals, Antioxidants, Biopterins, Cerebellum, Humans, Interneurons, Iron, Parkinson Disease, Receptors, Transferrin, Superoxides, Signal Transduction, 1-Methyl-4-phenylpyridinium, Apoptosis, Reactive Oxygen Species, Nitric Oxide Synthase, Mitochondrial Proteins, Electron Transport Complex I, Rats, Nitric Oxide Synthase Type I
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