Cytosolic NADH-NAD + Redox Visualized in Brain Slices by Two-Photon Fluorescence Lifetime Biosensor Imaging
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AIM: Cytosolic NADH-NAD(+) redox state is central to cellular metabolism and a valuable indicator of glucose and lactate metabolism in living cells. Here we sought to quantitatively determine NADH-NAD(+) redox in live cells and brain tissue using a fluorescence lifetime imaging of the genetically-encoded single-fluorophore biosensor Peredox. RESULTS: We show that Peredox exhibits a substantial change in its fluorescence lifetime over its sensing range of NADH-NAD(+) ratio. This allows changes in cytosolic NADH redox to be visualized in living cells using a two-photon scanning microscope with fluorescence lifetime imaging capabilities (2p-FLIM), using time-correlated single photon counting. INNOVATION: Because the lifetime readout is absolutely calibrated (in nanoseconds) and is independent of sensor concentration, we demonstrate that quantitative assessment of NADH redox is possible using a single fluorophore biosensor. CONCLUSION: Imaging of the sensor in mouse hippocampal brain slices reveals that astrocytes are typically much more reduced (with higher NADH:NAD(+) ratio) than neurons under basal conditions, consistent with the hypothesis that astrocytes are more glycolytic than neurons. Antioxid. Redox Signal. 25, 553-563.
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Use of pure lactate as an alternative fuel, rather than a redox-balanced mixture of lactate and pyruvate, abnormally elevates the low cytosolic NADH redox ratio in neurons.
“However, the use of pure lactate as an alternative fuel, rather than a redox-balanced mixture of lactate and pyruvate, abnormally elevates the low cytosolic NADH redox ratio in neurons (seen in vitro by Hung et al. [2011] and Mongeon et al. [2016] as well as in vivo by Díaz-García et al. [2017]); this decreases the rate of neuronal glycolysis in a way that would not represent the normal effect in”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Mongeon et al., 2016
In resting brain or quiescent brain slice, astrocytes appear to be more glycolytic than neurons.
“Consistent with most of the cultured cell studies, in resting brain or in quiescent brain slice astrocytes appear to be more glycolytic than neurons, with higher resting cytosolic NADH/NAD+ (NADHCYT) ratios (Mongeon et al., 2016) that predispose them to higher resting lactate/pyruvate ratios and higher resting lactate levels (Mächler et al., 2016).”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Mongeon et al., 2016
Astrocytes have higher resting cytosolic NADH/NAD+ (NADHCYT) ratios than neurons.
“Consistent with most of the cultured cell studies, in resting brain or in quiescent brain slice astrocytes appear to be more glycolytic than neurons, with higher resting cytosolic NADH/NAD+ (NADHCYT) ratios (Mongeon et al., 2016) that predispose them to higher resting lactate/pyruvate ratios and higher resting lactate levels (Mächler et al., 2016).”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Mongeon et al., 2016
Peredox fluorescence lifetime gives a direct report of cytosolic NADH:NAD+ ratio.
“The fluorescence lifetime (LT) of the sensor protein, measured in nanoseconds, gives a direct report of sensor occupancy and thus of the cytosolic NADH:NAD+ ratio (Mongeon et al., 2016).”
From Neuronal Stimulation Triggers Neuronal Glycolysis and Not Lactate Uptake (2017) · cites this paper as Mongeon et al., 2016
Even with this correction, the effect of some green signal from RCaMP1h still appears to produce some shift of the baseline lifetime values for Peredox, compared to those seen in the absence of RCaMP1h.
“Even with this correction, the effect of some green signal from RCaMP1h still appears to produce some shift of the baseline lifetime values for Peredox, compared to those seen in the absence of RCaMP1h (Mongeon et al., 2016).”
From Neuronal Stimulation Triggers Neuronal Glycolysis and Not Lactate Uptake (2017) · cites this paper as Mongeon et al., 2016
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- Authors
- Mongeon, R., Venkatachalam, V., & Yellen, G.
- Affiliations
- Harvard University (US)
- ORCID
- Yellen, Gary
- Venue
- Antioxidants & Redox Signaling
- Publisher
- SAGE Publications
- Published
- 2016-10
- Volume
- 25
- Issue
- 10
- Pages
- 553-563
- ISSN
- 1523-0864 (ISSN-L)
- 1557-7716
- PMC
- PMC5041510
- OpenAlex
- W2305213932
- Cited by
- 100
- References
- 28
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 12 · 2023: 11 · 2022: 9 · 2021: 8 · 2020: 9 · 2019: 6 · 2018: 9 · 2017: 8 · 2016: 4
- FWCI
- 5.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antioxidants and Redox Signaling (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (T32GM007753)
- National Institute of Neurological Disorders and Stroke (R01NS055031, F32NS080455)
- National Institute of Biomedical Imaging and Bioengineering (DP1EB016985)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Advanced Fluorescence Microscopy Techniques
- Physical Sciences › Chemistry › Spectroscopy › Molecular Sensors and Ion Detection
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- fluorescence lifetime imaging, two-photon microscopy, astrocytes, neurons, glycolysis, glucose metabolism, lactate metabolism, brain energy metabolism
- MeSH terms
- Animals, Astrocytes, Cytosol, Glucose, Glycolysis, Hippocampus, NAD, Neurons, Oxidation-Reduction, Biosensing Techniques, Lactic Acid, 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.
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