Evidence for redox regulation of cytochrome c release during programmed neuronal death: antioxidant effects of protein synthesis and caspase inhibition
Open accessAbstract
Sympathetic neurons die by apoptosis when they are deprived of nerve growth factor (NGF). Activation of caspases by cytochrome c released from mitochondria is central to this death. In this report we present evidence that cellular redox state regulates cytochrome c redistribution in these neurons. An increase of mitochondrial-produced reactive oxygen species (ROS) occurred in rat sympathetic neurons in cell culture within 3 hr of NGF withdrawal. Caspase inhibitors blocked this ROS burst. By 6 hr after NGF deprivation, glutathione (GSH) levels had increased, neutralizing elevated hydrogen peroxide levels and returning cellular redox state to basal levels. By 12 hr after deprivation, ROS levels had again increased and remained elevated during the rest of the apoptotic process. The later ROS burst appeared to have both caspase-dependent and caspase-independent components and was coincident with the period of cytochrome c release. Inhibition of protein synthesis with cycloheximide (CHX) and treatment with the antioxidant compound, N-acetyl-l-cysteine (l-NAC), blocked both the early and late ROS bursts by increasing cellular GSH levels (Ratan et al., 1994; Tan et al., 1998). Both compounds, and a membrane-permeant form of GSH, also inhibited cytochrome c release and death. Treatment of NGF, CHX-, l-NAC-, and GSH-saved cells with hydrogen peroxide caused rapid cytochrome c release. These data suggest a role for cellular redox state in regulating cytochrome c release during apoptosis induced by NGF withdrawal.
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CM-H2DCFDA is trapped in neurons, is insensitive to pH changes within the physiological range, and is not photo-oxidized by the laser power and exposure time used in these experiments.
“This characterization shows that CM-H2DCFDA is trapped in neurons, is insensitive to pH changes within the physiological range, and is not photo-oxidized by the laser power and exposure time used in these experiments.”
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 Kirkland and Franklin, 2001
The ROS measurement section (page unavailable) says CM-H2DCFDA is trapped inside cells and reports no significant leakage from neurons. The mitochondrial ROS section finds that the acidification tested did not quench the dye, but does not establish insensitivity across the physiological pH range. The ROS measurement section calls the dye relatively insensitive to photo-oxidation at low laser intensity; it does not say photo-oxidation was absent at the laser power and exposure time claimed. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe intrinsic apoptotic pathway may involve mitochondrial RS generation.
“Because the intrinsic apoptotic pathway may involve mitochondrial RS generation (Kirkland et al., 2001), we hypothesized that the decrease in oxidative stress caused by MitoQ treatment may prevent aberrant caspase activity in the 3xTg-AD model (Rohn et al., 2008).”
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 Kirkland et al., 2001
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Cites
Griffith, O. W., & Meister, A. (1979) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)35980-5 · Cited by 1,683 · see citing works
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Research works printed but not linked: 2
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Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling.
Lee, J., Giordano, S., & Zhang, J. (2012) · Biochemical Journal · doi:10.1042/bj20111451 · Cited by 1,438 · see citing works
McManus, 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
Self-citationBayir, H., Fadeel, B., Palladino, M. J., Witasp, E., Kurnikov, I. V., Tyurina, Y. Y., Tyurin, V. A., Amoscato, A. A., Jiang, J., Kochanek, P. M., et al. (2006) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2006.03.002 · Cited by 175 · see citing works
Young, M. L., & Franklin, J. L. (2019) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2019.103409 · Cited by 120 · see citing works
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- Authors
- Kirkland, R. A., & Franklin, J. L.
- Affiliations
- University of Wisconsin–Madison (US)
- ORCID
- Franklin, James L.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2001-03-15
- Volume
- 21
- Issue
- 6
- Pages
- 1949-1963
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6762616
- OpenAlex
- W1612119967
- Cited by
- 126
- References
- 1
- Citations by year
- 2026: 2 · 2024: 1 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 2 · 2019: 6 · 2018: 1 · 2017: 3 · 2016: 2 · 2015: 3 · 2014: 3 · 2013: 5 · 2012: 6
- FWCI
- 3.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (NS37110)
- National Institute of Neurological Disorders and Stroke (R29NS037110, NS37110, R01NS037110)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- cytochrome c release, redox regulation, apoptosis, sympathetic neurons, nerve growth factor deprivation, reactive oxygen species, glutathione, caspase inhibition, cycloheximide, N-acetylcysteine, hydrogen peroxide, mitochondrial reactive oxygen species, protein synthesis
- MeSH terms
- Animals, Antioxidants, Cell Survival, Cells, Cultured, Cytochrome c Group, Electron Transport, Fluorescent Dyes, Glutathione, Hydrogen Peroxide, Hydrogen-Ion Concentration, Intracellular Fluid, Neurons, Oxidation-Reduction, Protein Synthesis Inhibitors, Sympathetic Nervous System, Cysteine Proteinase Inhibitors, Rats, Sprague-Dawley, Apoptosis, Reactive Oxygen Species, Caspases, Nerve Growth Factor, Rats, Caspase Inhibitors
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