Physiology-based kinetic modeling of neuronal energy metabolism unravels the molecular basis of NAD(P)H fluorescence transients
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Imaging of the cellular fluorescence of the reduced form of nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) is one of the few metabolic readouts that enable noninvasive and time-resolved monitoring of the functional status of mitochondria in neuronal tissues. Stimulation-induced transient changes in NAD(P)H fluorescence intensity frequently display a biphasic characteristic that is influenced by various molecular processes, e.g., intracellular calcium dynamics, tricarboxylic acid cycle activity, the malate-aspartate shuttle, the glycerol-3-phosphate shuttle, oxygen supply or adenosine triphosphate (ATP) demand. To evaluate the relative impact of these processes, we developed and validated a detailed physiologic mathematical model of the energy metabolism of neuronal cells and used the model to simulate metabolic changes of single cells and tissue slices under different settings of stimulus-induced activity and varying nutritional supply of glucose, pyruvate or lactate. Notably, all experimentally determined NAD(P)H responses could be reproduced with one and the same generic cellular model. Our computations reveal that (1) cells with quite different metabolic status may generate almost identical NAD(P)H responses and (2) cells of the same type may quite differently contribute to aggregate NAD(P)H responses recorded in brain slices, depending on the spatial location within the tissue. Our computational approach reconciles different and sometimes even controversial experimental findings and improves our mechanistic understanding of the metabolic changes underlying live-cell NAD(P)H fluorescence transients.
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NAD(P)H autofluorescence is almost certainly dominated by mitochondrial NADH.
“The NAD(P)H autofluorescence is almost certainly dominated by mitochondrial NADH (Brennan et al., 2006; Shuttleworth, 2010; Berndt et al., 2015).”
From Neuronal Stimulation Triggers Neuronal Glycolysis and Not Lactate Uptake (2017) · cites this paper as Berndt et al., 2015
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- Authors
- Berndt, N., Kann, O., & Holzhütter, H.-G.
- Affiliations
- Charité – Universitätsmedizin Berlin (DE)
- Heidelberg University (DE)
- Corresponding author
- Kann, Oliver
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2015-04-22
- Volume
- 35
- Issue
- 9
- Pages
- 1494-1506
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- PMC
- PMC4640339
- OpenAlex
- W2056633409
- Cited by
- 56
- References
- 58
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 10 · 2023: 5 · 2022: 2 · 2021: 7 · 2020: 1 · 2019: 1 · 2018: 7 · 2017: 4 · 2016: 4
- FWCI
- 2.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Advanced Fluorescence Microscopy Techniques
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- NAD(P)H fluorescence, neuronal energy metabolism, kinetic modeling, mitochondrial function, intracellular calcium dynamics, TCA cycle, malate-aspartate shuttle, glycerol-3-phosphate shuttle, ATP demand, brain slices
- MeSH terms
- Animals, Energy Metabolism, Fluorescence, Humans, Models, Neurological, NADP, Neurons
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