Different Responses of Astrocytes and Neurons to Nitric Oxide: The Role of Glycolytically Generated ATP in Astrocyte Protection
Open accessAbstract
It was recently proposed that in Jurkat cells, after inhibition of respiration by NO, glycolytically generated ATP plays a critical role in preventing the collapse of mitochondrial membrane potential (Δψ m ) and thus apoptotic cell death. We have investigated this observation further in primary cultures of rat cortical neurons and astrocytes—cell types that differ greatly in their glycolytic capacity. Continuous and significant (≈85%) inhibition of respiration by NO (1.4 μM at 175 μM O 2 ) generated by [(z)-1-[2-aminoethyl]- N -[2-ammonioethyl]amino]diazen-1-ium-1,2 diolate (DETA-NO) initially (10 min) depleted ATP concentrations by ≈25% in both cell types and increased the rate of glycolysis in astrocytes but not in neurons. Activation of glycolysis in astrocytes, as judged by lactate production, prevented further ATP depletion, whereas in neurons, which do not invoke this mechanism, there was a progressive decrease in ATP concentrations over the next 60 min. During this time, there was a persistent mitochondrial hyperpolarization and absence of apoptotic cell death in astrocytes, whereas in the neurons there was a progressive fall in Δψ m and increased apoptosis. After glucose deprivation or treatment with inhibitors of the F 1 F 0 -ATPase and adenine nucleotide translocase, astrocytes responded to NO with a fall in Δψ m and apoptotic cell death similar to the response in neurons. Finally, although treatment of astrocytes with NO partially prevented staurosporin-induced collapse in Δψ m and cell death, NO and staurosporin synergized in decreasing Δψ m and inducing apoptosis in neurons. These results demonstrate that although inhibition of cellular respiration by NO leads to neurotoxicity, it may also result in initial neuroprotection, depending on the glycolytic capacity of the particular cell.
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Previous studies have shown that the inhibition of mitochondrial respiration increased the rate of glycolysis in astrocytes but not neurons.
“Accordingly, previous studies have shown that the inhibition of mitochondrial respiration increased the rate of glycolysis in astrocytes but not neurons [56].”
From Proliferating Astrocytes in Primary Culture Do Not Depend upon Mitochondrial Respiratory Complex I Activity or Oxidative Phosphorylation (2023) · cites this paper as [56]
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- Authors
- Almeida, A., Almeida, J., Bolaños, J. P., & Moncada, S.
- Affiliations
- Departamento de Bioquímica y Biología Molecular and Departamento de Medicina, Universidad de Salamanca, and Unidad de Investigación, Hospital Universitario de Salamanca, 37007 Salamanca, Spain; and The Wolfson Institute for Biomedical Research, University College London, London WCIE 6BT, United Kingdom
- Universidad de Salamanca (ES)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2001-12-11
- Volume
- 98
- Issue
- 26
- Pages
- 15294-15299
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC65023
- OpenAlex
- W2164016655
- Cited by
- 423
- References
- 2
- Citations by year
- 2026: 5 · 2025: 15 · 2024: 15 · 2023: 23 · 2022: 10 · 2021: 16 · 2020: 18 · 2019: 17 · 2018: 13 · 2017: 18 · 2016: 23 · 2015: 19 · 2014: 13 · 2013: 15 · 2012: 15
- FWCI
- 6.63
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- 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 › Neuroscience › Neurology › Neurological Disorders and Treatments
- Keywords
- nitric oxide, astrocytes, cortical neurons, mitochondrial membrane potential, apoptosis, respiration inhibition, neuroprotection, neurotoxicity, lactic acid production, staurosporine, F1F0-ATPase, adenine nucleotide translocase, glucose deprivation, DETA/NO
- MeSH terms
- Adenosine Triphosphate, Animals, Astrocytes, Cells, Cultured, Cerebral Cortex, Glycolysis, Membrane Potentials, Mitochondria, Neurons, Nitric Oxide, Oxygen Consumption, Rats, Wistar, Apoptosis, Staurosporine, Rats
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