Abstract

Carbonyl cyanide-p-trifluoro methoxyphenylhydrazone (FCCP) is a well-known mitochondrial uncoupling agent. We examined FCCP-induced fluorescence quenching of reduced nicotinamide adenine dinucleotide / nicotinamide adenine dinucleotide phosphate (NAD(P)H) in solution and in cultured HeLa cells in a wide range of FCCP concentrations from 50 to 1000µM. A non-invasive label-free method of hyperspectral imaging of cell autofluorescence combined with unsupervised unmixing was used to separately isolate the emissions of free and bound NAD(P)H from cell autofluorescence. Hyperspectral image analysis of FCCP-treated HeLa cells confirms that this agent selectively quenches fluorescence of free and bound NAD(P)H in a broad range of concentrations. This is confirmed by the measurements of average NAD/NADH and NADP/NADPH content in cells. FCCP quenching of free NAD(P)H in cells and in solution is found to be similar, but quenching of bound NAD(P)H in cells is attenuated compared to solution quenching possibly due to a contribution from the metabolic and/or antioxidant response in cells. Chemical quenching of NAD(P)H fluorescence by FCCP validates the results of unsupervised unmixing of cell autofluorescence.

© 2017 Optical Society of America

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2016 (1)

M. E. Gosnell, A. G. Anwer, J. C. Cassano, C. M. Sue, and E. M. Goldys, “Functional hyperspectral imaging captures subtle details of cell metabolism in olfactory neurosphere cells, disease-specific models of neurodegenerative disorders,” Biochim. Biophys. Acta 1863(1), 56–63 (2016).
[Crossref] [PubMed]

2015 (3)

W. Zeng, P. Liu, W. Pan, S. R. Singh, and Y. Wei, “Hypoxia and hypoxia inducible factors in tumor metabolism,” Cancer Lett. 356(22 Pt A), 263–267 (2015).
[Crossref] [PubMed]

C. Stringari, H. Wang, M. Geyfman, V. Crosignani, V. Kumar, J. S. Takahashi, B. Andersen, and E. Gratton, “In vivo single-cell detection of metabolic oscillations in stem cells,” Cell Reports 10(1), 1–7 (2015).
[Crossref] [PubMed]

R. Datta, A. Alfonso-García, R. Cinco, and E. Gratton, “Fluorescence lifetime imaging of endogenous biomarker of oxidative stress,” Sci. Rep. 5, 9848 (2015), doi:.
[Crossref] [PubMed]

2012 (3)

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic imaging using two-photon excited NADH intensity and fluorescence lifetime imaging,” Microsc. Microanal. 18(4), 761–770 (2012).
[Crossref] [PubMed]

C. Stringari, R. A. Edwards, K. T. Pate, M. L. Waterman, P. J. Donovan, and E. Gratton, “Metabolic trajectory of cellular differentiation in small intestine by Phasor Fluorescence Lifetime Microscopy of NADH,” Sci. Rep. 2, 568 (2012).
[Crossref] [PubMed]

J. M. Nascimento and J. M. Bioucas-Dias, “Hyperspectral unmixing based on mixtures of Dirichlet components,” IEEE Trans. Geosc Remot. Sens. 50(3), 863–878 (2012).
[Crossref]

2011 (1)

J. P. Monteiro, A. F. Martins, M. Lúcio, S. Reis, C. F. Geraldes, P. J. Oliveira, and A. S. Jurado, “Interaction of carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) with lipid membrane systems: a biophysical approach with relevance to mitochondrial uncoupling,” J. Bioenerg. Biomembr. 43(3), 287–298 (2011).
[Crossref] [PubMed]

2009 (2)

M. G. Vander Heiden, L. C. Cantley, and C. B. Thompson, “Understanding the Warburg effect: the metabolic requirements of cell proliferation,” Science 324(5930), 1029–1033 (2009).
[Crossref] [PubMed]

L. Z. Li, H. N. Xu, M. Ranji, S. Nioka, and B. Chance, “Mitochondrial redox imaging for cancer diagnostic and therapeutic studies,” J. Innov. Opt. Health Sci. 2(4), 325–341 (2009).
[Crossref] [PubMed]

2007 (3)

D. Schweitzer, S. Schenke, M. Hammer, F. Schweitzer, S. Jentsch, E. Birckner, W. Becker, and A. Bergmann, “Towards metabolic mapping of the human retina,” Microsc. Res. Tech. 70(5), 410–419 (2007).
[Crossref] [PubMed]

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
[Crossref] [PubMed]

D. R. Jérôme, F. Maureen, W. Johan, A. Perpèteb, P. Julien, and J. Denis, “Towards the understanding of the absorption spectra of NAD(P)H/NAD(P)+ as a common indicator of dehydrogenase enzymatic activity,” Chem. Phys. Lett. 450(1–3), 119–122 (2007).

2006 (2)

J. P. Brennan, R. G. Berry, M. Baghai, M. R. Duchen, and M. J. Shattock, “FCCP is cardioprotective at concentrations that cause mitochondrial oxidation without detectable depolarisation,” Cardiovasc. Res. 72(2), 322–330 (2006).
[Crossref] [PubMed]

A. Mayevsky and G. G. Rogatsky, “Mitochondrial function in vivo evaluated by NADH fluorescence: from animal models to human studies,” Am. J. Physiol. Cell Physiol. 292(2), C615–C640 (2006).
[Crossref] [PubMed]

2005 (1)

K. Blinova, S. Carroll, S. Bose, A. V. Smirnov, J. J. Harvey, J. R. Knutson, and R. S. Balaban, “Distribution of mitochondrial NADH fluorescence lifetimes: steady-state kinetics of matrix NADH interactions,” Biochemistry 44(7), 2585–2594 (2005).
[Crossref] [PubMed]

2003 (1)

C. C. Fjeld, W. T. Birdsong, and R. H. Goodman, “Differential binding of NAD+ and NADH allows the transcriptional corepressor carboxyl-terminal binding protein to serve as a metabolic sensor,” Proc. Natl. Acad. Sci. U.S.A. 100(16), 9202–9207 (2003).
[Crossref] [PubMed]

2002 (2)

P. K. Hammen, A. Allali-Hassani, K. Hallenga, T. D. Hurley, and H. Weiner, “Multiple conformations of NAD and NADH when bound to human cytosolic and mitochondrial aldehyde dehydrogenase,” Biochemistry 41(22), 7156–7168 (2002).
[Crossref] [PubMed]

N. Keshava and J. F. Mustard, “Spectral unmixing,” Sig. Proc. Mag., IEEE 19(1), 44–57 (2002).
[Crossref]

2001 (1)

D. Manolakis, C. Siracusa, and G. Shaw, “Hyperspectral subpixel target detection using the linear mixing model,” IEEE Trans. Geosc Remot. Sens 39(7), 1392–1409 (2001).
[Crossref]

2000 (1)

D. G. Nicholls and S. L. Budd, “Mitochondria and neuronal survival,” Physiol. Rev. 80(1), 315–360 (2000).
[PubMed]

1999 (1)

A. S. Galkin, V. G. Grivennikova, and A. D. Vinogradov, “→H+/2e- stoichiometry in NADH-quinone reductase reactions catalyzed by bovine heart submitochondrial particles,” FEBS Lett. 451(2), 157–161 (1999).
[Crossref] [PubMed]

1998 (4)

K. J. Buckler and R. D. Vaughan-Jones, “Effects of mitochondrial uncouplers on intracellular calcium, pH and membrane potential in rat carotid body type I cells,” J. Physiol. 513(3), 819–833 (1998).
[Crossref] [PubMed]

E. J. Griffiths, H. Lin, and M. S. Suleiman, “NADH fluorescence in isolated guinea-pig and rat cardiomyocytes exposed to low or high stimulation rates and effect of metabolic inhibition with cyanide,” Biochem. Pharmacol. 56(2), 173–179 (1998).
[Crossref] [PubMed]

H. Andersson, T. Baechi, M. Hoechl, and C. Richter, “Autofluorescence of living cells,” J. Microsc. 191(1), 1–7 (1998).
[Crossref] [PubMed]

S. R. Piersma, A. J. W. G. Visser, S. de Vries, and J. A. Duine, “Optical spectroscopy of nicotinoprotein alcohol dehydrogenase from Amycolatopsis methanolica: a comparison with horse liver alcohol dehydrogenase and UDP-galactose epimerase,” Biochemistry 37(9), 3068–3077 (1998).
[Crossref] [PubMed]

1996 (1)

R. J. Paul and H. Schneckenburger, “Oxygen concentration and the oxidation-reduction state of yeast: determination of free/bound NADH and flavins by time-resolved spectroscopy,” Naturwissenschaften 83(1), 32–35 (1996).
[Crossref] [PubMed]

1995 (1)

P. G. Cordeiro, R. E. Kirschner, Q.-Y. Hu, J. J. Chiao, H. Savage, R. R. Alfano, L. A. Hoffman, and D. A. Hidalgo, “Ultraviolet excitation fluorescence spectroscopy: a noninvasive method for the measurement of redox changes in ischemic myocutaneous flaps,” Plast. Reconstr. Surg. 96(3), 673–680 (1995).
[Crossref] [PubMed]

1994 (1)

J. C. Harsanyi and C.-I. Chang, “Hyperspectral image classification and dimensionality reduction: an orthogonal subspace projection approach,” IEEE Trans. Geosci. Remot. Sens. 32(4), 779–785 (1994).
[Crossref]

1989 (2)

J. Eng, R. M. Lynch, and R. S. Balaban, “Nicotinamide adenine dinucleotide fluorescence spectroscopy and imaging of isolated cardiac myocytes,” Biophys. J. 55(4), 621–630 (1989).
[Crossref] [PubMed]

M. Frigge, D. C. Hoaglin, and B. Iglewicz, “Some Implementations of the Boxplot,” Am. Stat. 43(1), 50–54 (1989).

1988 (1)

Y. Benjamini, “Opening the Box of a Boxplot,” Stat 42(4), 257–262 (1988).

1985 (1)

L. Lindqvist, B. Czochralska, and I. Grigorov, “Determination of the mechanism of photoionization of NADH in aqeous solution on laser excitation at 355 nm,” Chem. Phys. Lett. 119(6), 494–498 (1985).
[Crossref]

1984 (1)

P. D. Reiss, P. F. Zuurendonk, and R. L. Veech, “Measurement of tissue purine, pyrimidine, and other nucleotides by radial compression high-performance liquid chromatography,” Anal. Biochem. 140(1), 162–171 (1984).
[Crossref] [PubMed]

1978 (1)

B. Chance and M. Lieberman, “Intrinsic fluorescence emission from the cornea at low temperatures: evidence of mitochondrial signals and their differing redox states in epithelial and endothelial sides,” Exp. Eye Res. 26(1), 111–117 (1978).
[Crossref] [PubMed]

1977 (1)

R. J. Kessler, H. Vande Zande, C. A. Tyson, G. A. Blondin, J. Fairfield, P. Glasser, and D. E. Green, “Uncouplers and the molecular mechanism of uncoupling in mitochondria,” Proc. Natl. Acad. Sci. U.S.A. 74(6), 2241–2245 (1977).
[Crossref] [PubMed]

1967 (1)

S. S. Lehrer, “The selective quenching of tryptophan fluorescence in proteins by iodide ion: lysozyme in the presence and absence of substrate,” Biochem. Biophys. Res. Commun. 29(5), 767–772 (1967).
[Crossref] [PubMed]

1962 (2)

B. Chance, P. Cohen, F. Jobsis, and B. Schoener, “Intracellular oxidation-reduction states in vivo,” Science 137(3529), 499–508 (1962).
[Crossref] [PubMed]

R. W. Estabrook, “Fluorometric measurement of reduced pyridine nucleotide in cellular and subcellular particles,” Anal. Biochem. 4(3), 231–245 (1962).
[Crossref] [PubMed]

Alfano, R. R.

P. G. Cordeiro, R. E. Kirschner, Q.-Y. Hu, J. J. Chiao, H. Savage, R. R. Alfano, L. A. Hoffman, and D. A. Hidalgo, “Ultraviolet excitation fluorescence spectroscopy: a noninvasive method for the measurement of redox changes in ischemic myocutaneous flaps,” Plast. Reconstr. Surg. 96(3), 673–680 (1995).
[Crossref] [PubMed]

Alfonso-García, A.

R. Datta, A. Alfonso-García, R. Cinco, and E. Gratton, “Fluorescence lifetime imaging of endogenous biomarker of oxidative stress,” Sci. Rep. 5, 9848 (2015), doi:.
[Crossref] [PubMed]

Allali-Hassani, A.

P. K. Hammen, A. Allali-Hassani, K. Hallenga, T. D. Hurley, and H. Weiner, “Multiple conformations of NAD and NADH when bound to human cytosolic and mitochondrial aldehyde dehydrogenase,” Biochemistry 41(22), 7156–7168 (2002).
[Crossref] [PubMed]

Andersen, B.

C. Stringari, H. Wang, M. Geyfman, V. Crosignani, V. Kumar, J. S. Takahashi, B. Andersen, and E. Gratton, “In vivo single-cell detection of metabolic oscillations in stem cells,” Cell Reports 10(1), 1–7 (2015).
[Crossref] [PubMed]

Andersson, H.

H. Andersson, T. Baechi, M. Hoechl, and C. Richter, “Autofluorescence of living cells,” J. Microsc. 191(1), 1–7 (1998).
[Crossref] [PubMed]

Anwer, A. G.

M. E. Gosnell, A. G. Anwer, J. C. Cassano, C. M. Sue, and E. M. Goldys, “Functional hyperspectral imaging captures subtle details of cell metabolism in olfactory neurosphere cells, disease-specific models of neurodegenerative disorders,” Biochim. Biophys. Acta 1863(1), 56–63 (2016).
[Crossref] [PubMed]

Baechi, T.

H. Andersson, T. Baechi, M. Hoechl, and C. Richter, “Autofluorescence of living cells,” J. Microsc. 191(1), 1–7 (1998).
[Crossref] [PubMed]

Baghai, M.

J. P. Brennan, R. G. Berry, M. Baghai, M. R. Duchen, and M. J. Shattock, “FCCP is cardioprotective at concentrations that cause mitochondrial oxidation without detectable depolarisation,” Cardiovasc. Res. 72(2), 322–330 (2006).
[Crossref] [PubMed]

Balaban, R. S.

K. Blinova, S. Carroll, S. Bose, A. V. Smirnov, J. J. Harvey, J. R. Knutson, and R. S. Balaban, “Distribution of mitochondrial NADH fluorescence lifetimes: steady-state kinetics of matrix NADH interactions,” Biochemistry 44(7), 2585–2594 (2005).
[Crossref] [PubMed]

J. Eng, R. M. Lynch, and R. S. Balaban, “Nicotinamide adenine dinucleotide fluorescence spectroscopy and imaging of isolated cardiac myocytes,” Biophys. J. 55(4), 621–630 (1989).
[Crossref] [PubMed]

Becker, W.

D. Schweitzer, S. Schenke, M. Hammer, F. Schweitzer, S. Jentsch, E. Birckner, W. Becker, and A. Bergmann, “Towards metabolic mapping of the human retina,” Microsc. Res. Tech. 70(5), 410–419 (2007).
[Crossref] [PubMed]

Benjamini, Y.

Y. Benjamini, “Opening the Box of a Boxplot,” Stat 42(4), 257–262 (1988).

Bergmann, A.

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C. C. Fjeld, W. T. Birdsong, and R. H. Goodman, “Differential binding of NAD+ and NADH allows the transcriptional corepressor carboxyl-terminal binding protein to serve as a metabolic sensor,” Proc. Natl. Acad. Sci. U.S.A. 100(16), 9202–9207 (2003).
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J. P. Brennan, R. G. Berry, M. Baghai, M. R. Duchen, and M. J. Shattock, “FCCP is cardioprotective at concentrations that cause mitochondrial oxidation without detectable depolarisation,” Cardiovasc. Res. 72(2), 322–330 (2006).
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M. E. Gosnell, A. G. Anwer, J. C. Cassano, C. M. Sue, and E. M. Goldys, “Functional hyperspectral imaging captures subtle details of cell metabolism in olfactory neurosphere cells, disease-specific models of neurodegenerative disorders,” Biochim. Biophys. Acta 1863(1), 56–63 (2016).
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L. Z. Li, H. N. Xu, M. Ranji, S. Nioka, and B. Chance, “Mitochondrial redox imaging for cancer diagnostic and therapeutic studies,” J. Innov. Opt. Health Sci. 2(4), 325–341 (2009).
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B. Chance and M. Lieberman, “Intrinsic fluorescence emission from the cornea at low temperatures: evidence of mitochondrial signals and their differing redox states in epithelial and endothelial sides,” Exp. Eye Res. 26(1), 111–117 (1978).
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B. Chance, P. Cohen, F. Jobsis, and B. Schoener, “Intracellular oxidation-reduction states in vivo,” Science 137(3529), 499–508 (1962).
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J. C. Harsanyi and C.-I. Chang, “Hyperspectral image classification and dimensionality reduction: an orthogonal subspace projection approach,” IEEE Trans. Geosci. Remot. Sens. 32(4), 779–785 (1994).
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R. Datta, A. Alfonso-García, R. Cinco, and E. Gratton, “Fluorescence lifetime imaging of endogenous biomarker of oxidative stress,” Sci. Rep. 5, 9848 (2015), doi:.
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L. Lindqvist, B. Czochralska, and I. Grigorov, “Determination of the mechanism of photoionization of NADH in aqeous solution on laser excitation at 355 nm,” Chem. Phys. Lett. 119(6), 494–498 (1985).
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R. Datta, A. Alfonso-García, R. Cinco, and E. Gratton, “Fluorescence lifetime imaging of endogenous biomarker of oxidative stress,” Sci. Rep. 5, 9848 (2015), doi:.
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C. Stringari, R. A. Edwards, K. T. Pate, M. L. Waterman, P. J. Donovan, and E. Gratton, “Metabolic trajectory of cellular differentiation in small intestine by Phasor Fluorescence Lifetime Microscopy of NADH,” Sci. Rep. 2, 568 (2012).
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J. P. Brennan, R. G. Berry, M. Baghai, M. R. Duchen, and M. J. Shattock, “FCCP is cardioprotective at concentrations that cause mitochondrial oxidation without detectable depolarisation,” Cardiovasc. Res. 72(2), 322–330 (2006).
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S. R. Piersma, A. J. W. G. Visser, S. de Vries, and J. A. Duine, “Optical spectroscopy of nicotinoprotein alcohol dehydrogenase from Amycolatopsis methanolica: a comparison with horse liver alcohol dehydrogenase and UDP-galactose epimerase,” Biochemistry 37(9), 3068–3077 (1998).
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C. Stringari, R. A. Edwards, K. T. Pate, M. L. Waterman, P. J. Donovan, and E. Gratton, “Metabolic trajectory of cellular differentiation in small intestine by Phasor Fluorescence Lifetime Microscopy of NADH,” Sci. Rep. 2, 568 (2012).
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M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
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M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
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C. C. Fjeld, W. T. Birdsong, and R. H. Goodman, “Differential binding of NAD+ and NADH allows the transcriptional corepressor carboxyl-terminal binding protein to serve as a metabolic sensor,” Proc. Natl. Acad. Sci. U.S.A. 100(16), 9202–9207 (2003).
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M. Frigge, D. C. Hoaglin, and B. Iglewicz, “Some Implementations of the Boxplot,” Am. Stat. 43(1), 50–54 (1989).

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A. S. Galkin, V. G. Grivennikova, and A. D. Vinogradov, “→H+/2e- stoichiometry in NADH-quinone reductase reactions catalyzed by bovine heart submitochondrial particles,” FEBS Lett. 451(2), 157–161 (1999).
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M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
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J. P. Monteiro, A. F. Martins, M. Lúcio, S. Reis, C. F. Geraldes, P. J. Oliveira, and A. S. Jurado, “Interaction of carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) with lipid membrane systems: a biophysical approach with relevance to mitochondrial uncoupling,” J. Bioenerg. Biomembr. 43(3), 287–298 (2011).
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Geyfman, M.

C. Stringari, H. Wang, M. Geyfman, V. Crosignani, V. Kumar, J. S. Takahashi, B. Andersen, and E. Gratton, “In vivo single-cell detection of metabolic oscillations in stem cells,” Cell Reports 10(1), 1–7 (2015).
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R. J. Kessler, H. Vande Zande, C. A. Tyson, G. A. Blondin, J. Fairfield, P. Glasser, and D. E. Green, “Uncouplers and the molecular mechanism of uncoupling in mitochondria,” Proc. Natl. Acad. Sci. U.S.A. 74(6), 2241–2245 (1977).
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Goldys, E. M.

M. E. Gosnell, A. G. Anwer, J. C. Cassano, C. M. Sue, and E. M. Goldys, “Functional hyperspectral imaging captures subtle details of cell metabolism in olfactory neurosphere cells, disease-specific models of neurodegenerative disorders,” Biochim. Biophys. Acta 1863(1), 56–63 (2016).
[Crossref] [PubMed]

Goodman, R. H.

C. C. Fjeld, W. T. Birdsong, and R. H. Goodman, “Differential binding of NAD+ and NADH allows the transcriptional corepressor carboxyl-terminal binding protein to serve as a metabolic sensor,” Proc. Natl. Acad. Sci. U.S.A. 100(16), 9202–9207 (2003).
[Crossref] [PubMed]

Gosnell, M. E.

M. E. Gosnell, A. G. Anwer, J. C. Cassano, C. M. Sue, and E. M. Goldys, “Functional hyperspectral imaging captures subtle details of cell metabolism in olfactory neurosphere cells, disease-specific models of neurodegenerative disorders,” Biochim. Biophys. Acta 1863(1), 56–63 (2016).
[Crossref] [PubMed]

Gratton, E.

C. Stringari, H. Wang, M. Geyfman, V. Crosignani, V. Kumar, J. S. Takahashi, B. Andersen, and E. Gratton, “In vivo single-cell detection of metabolic oscillations in stem cells,” Cell Reports 10(1), 1–7 (2015).
[Crossref] [PubMed]

R. Datta, A. Alfonso-García, R. Cinco, and E. Gratton, “Fluorescence lifetime imaging of endogenous biomarker of oxidative stress,” Sci. Rep. 5, 9848 (2015), doi:.
[Crossref] [PubMed]

C. Stringari, R. A. Edwards, K. T. Pate, M. L. Waterman, P. J. Donovan, and E. Gratton, “Metabolic trajectory of cellular differentiation in small intestine by Phasor Fluorescence Lifetime Microscopy of NADH,” Sci. Rep. 2, 568 (2012).
[Crossref] [PubMed]

Green, D. E.

R. J. Kessler, H. Vande Zande, C. A. Tyson, G. A. Blondin, J. Fairfield, P. Glasser, and D. E. Green, “Uncouplers and the molecular mechanism of uncoupling in mitochondria,” Proc. Natl. Acad. Sci. U.S.A. 74(6), 2241–2245 (1977).
[Crossref] [PubMed]

Griffiths, E. J.

E. J. Griffiths, H. Lin, and M. S. Suleiman, “NADH fluorescence in isolated guinea-pig and rat cardiomyocytes exposed to low or high stimulation rates and effect of metabolic inhibition with cyanide,” Biochem. Pharmacol. 56(2), 173–179 (1998).
[Crossref] [PubMed]

Grigorov, I.

L. Lindqvist, B. Czochralska, and I. Grigorov, “Determination of the mechanism of photoionization of NADH in aqeous solution on laser excitation at 355 nm,” Chem. Phys. Lett. 119(6), 494–498 (1985).
[Crossref]

Grivennikova, V. G.

A. S. Galkin, V. G. Grivennikova, and A. D. Vinogradov, “→H+/2e- stoichiometry in NADH-quinone reductase reactions catalyzed by bovine heart submitochondrial particles,” FEBS Lett. 451(2), 157–161 (1999).
[Crossref] [PubMed]

Hallenga, K.

P. K. Hammen, A. Allali-Hassani, K. Hallenga, T. D. Hurley, and H. Weiner, “Multiple conformations of NAD and NADH when bound to human cytosolic and mitochondrial aldehyde dehydrogenase,” Biochemistry 41(22), 7156–7168 (2002).
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J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic imaging using two-photon excited NADH intensity and fluorescence lifetime imaging,” Microsc. Microanal. 18(4), 761–770 (2012).
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P. K. Hammen, A. Allali-Hassani, K. Hallenga, T. D. Hurley, and H. Weiner, “Multiple conformations of NAD and NADH when bound to human cytosolic and mitochondrial aldehyde dehydrogenase,” Biochemistry 41(22), 7156–7168 (2002).
[Crossref] [PubMed]

Hammer, M.

D. Schweitzer, S. Schenke, M. Hammer, F. Schweitzer, S. Jentsch, E. Birckner, W. Becker, and A. Bergmann, “Towards metabolic mapping of the human retina,” Microsc. Res. Tech. 70(5), 410–419 (2007).
[Crossref] [PubMed]

Harsanyi, J. C.

J. C. Harsanyi and C.-I. Chang, “Hyperspectral image classification and dimensionality reduction: an orthogonal subspace projection approach,” IEEE Trans. Geosci. Remot. Sens. 32(4), 779–785 (1994).
[Crossref]

Harvey, J. J.

K. Blinova, S. Carroll, S. Bose, A. V. Smirnov, J. J. Harvey, J. R. Knutson, and R. S. Balaban, “Distribution of mitochondrial NADH fluorescence lifetimes: steady-state kinetics of matrix NADH interactions,” Biochemistry 44(7), 2585–2594 (2005).
[Crossref] [PubMed]

Hecht, C.

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic imaging using two-photon excited NADH intensity and fluorescence lifetime imaging,” Microsc. Microanal. 18(4), 761–770 (2012).
[Crossref] [PubMed]

Hidalgo, D. A.

P. G. Cordeiro, R. E. Kirschner, Q.-Y. Hu, J. J. Chiao, H. Savage, R. R. Alfano, L. A. Hoffman, and D. A. Hidalgo, “Ultraviolet excitation fluorescence spectroscopy: a noninvasive method for the measurement of redox changes in ischemic myocutaneous flaps,” Plast. Reconstr. Surg. 96(3), 673–680 (1995).
[Crossref] [PubMed]

Hoaglin, D. C.

M. Frigge, D. C. Hoaglin, and B. Iglewicz, “Some Implementations of the Boxplot,” Am. Stat. 43(1), 50–54 (1989).

Hoechl, M.

H. Andersson, T. Baechi, M. Hoechl, and C. Richter, “Autofluorescence of living cells,” J. Microsc. 191(1), 1–7 (1998).
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Hoffman, L. A.

P. G. Cordeiro, R. E. Kirschner, Q.-Y. Hu, J. J. Chiao, H. Savage, R. R. Alfano, L. A. Hoffman, and D. A. Hidalgo, “Ultraviolet excitation fluorescence spectroscopy: a noninvasive method for the measurement of redox changes in ischemic myocutaneous flaps,” Plast. Reconstr. Surg. 96(3), 673–680 (1995).
[Crossref] [PubMed]

Hu, Q.-Y.

P. G. Cordeiro, R. E. Kirschner, Q.-Y. Hu, J. J. Chiao, H. Savage, R. R. Alfano, L. A. Hoffman, and D. A. Hidalgo, “Ultraviolet excitation fluorescence spectroscopy: a noninvasive method for the measurement of redox changes in ischemic myocutaneous flaps,” Plast. Reconstr. Surg. 96(3), 673–680 (1995).
[Crossref] [PubMed]

Hurley, T. D.

P. K. Hammen, A. Allali-Hassani, K. Hallenga, T. D. Hurley, and H. Weiner, “Multiple conformations of NAD and NADH when bound to human cytosolic and mitochondrial aldehyde dehydrogenase,” Biochemistry 41(22), 7156–7168 (2002).
[Crossref] [PubMed]

Iglewicz, B.

M. Frigge, D. C. Hoaglin, and B. Iglewicz, “Some Implementations of the Boxplot,” Am. Stat. 43(1), 50–54 (1989).

Jentsch, S.

D. Schweitzer, S. Schenke, M. Hammer, F. Schweitzer, S. Jentsch, E. Birckner, W. Becker, and A. Bergmann, “Towards metabolic mapping of the human retina,” Microsc. Res. Tech. 70(5), 410–419 (2007).
[Crossref] [PubMed]

Jérôme, D. R.

D. R. Jérôme, F. Maureen, W. Johan, A. Perpèteb, P. Julien, and J. Denis, “Towards the understanding of the absorption spectra of NAD(P)H/NAD(P)+ as a common indicator of dehydrogenase enzymatic activity,” Chem. Phys. Lett. 450(1–3), 119–122 (2007).

Jobsis, F.

B. Chance, P. Cohen, F. Jobsis, and B. Schoener, “Intracellular oxidation-reduction states in vivo,” Science 137(3529), 499–508 (1962).
[Crossref] [PubMed]

Johan, W.

D. R. Jérôme, F. Maureen, W. Johan, A. Perpèteb, P. Julien, and J. Denis, “Towards the understanding of the absorption spectra of NAD(P)H/NAD(P)+ as a common indicator of dehydrogenase enzymatic activity,” Chem. Phys. Lett. 450(1–3), 119–122 (2007).

Julien, P.

D. R. Jérôme, F. Maureen, W. Johan, A. Perpèteb, P. Julien, and J. Denis, “Towards the understanding of the absorption spectra of NAD(P)H/NAD(P)+ as a common indicator of dehydrogenase enzymatic activity,” Chem. Phys. Lett. 450(1–3), 119–122 (2007).

Jurado, A. S.

J. P. Monteiro, A. F. Martins, M. Lúcio, S. Reis, C. F. Geraldes, P. J. Oliveira, and A. S. Jurado, “Interaction of carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) with lipid membrane systems: a biophysical approach with relevance to mitochondrial uncoupling,” J. Bioenerg. Biomembr. 43(3), 287–298 (2011).
[Crossref] [PubMed]

Keely, P. J.

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
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Kessler, R. J.

R. J. Kessler, H. Vande Zande, C. A. Tyson, G. A. Blondin, J. Fairfield, P. Glasser, and D. E. Green, “Uncouplers and the molecular mechanism of uncoupling in mitochondria,” Proc. Natl. Acad. Sci. U.S.A. 74(6), 2241–2245 (1977).
[Crossref] [PubMed]

Kirschner, R. E.

P. G. Cordeiro, R. E. Kirschner, Q.-Y. Hu, J. J. Chiao, H. Savage, R. R. Alfano, L. A. Hoffman, and D. A. Hidalgo, “Ultraviolet excitation fluorescence spectroscopy: a noninvasive method for the measurement of redox changes in ischemic myocutaneous flaps,” Plast. Reconstr. Surg. 96(3), 673–680 (1995).
[Crossref] [PubMed]

Knutson, J. R.

K. Blinova, S. Carroll, S. Bose, A. V. Smirnov, J. J. Harvey, J. R. Knutson, and R. S. Balaban, “Distribution of mitochondrial NADH fluorescence lifetimes: steady-state kinetics of matrix NADH interactions,” Biochemistry 44(7), 2585–2594 (2005).
[Crossref] [PubMed]

Kumar, V.

C. Stringari, H. Wang, M. Geyfman, V. Crosignani, V. Kumar, J. S. Takahashi, B. Andersen, and E. Gratton, “In vivo single-cell detection of metabolic oscillations in stem cells,” Cell Reports 10(1), 1–7 (2015).
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S. S. Lehrer, “The selective quenching of tryptophan fluorescence in proteins by iodide ion: lysozyme in the presence and absence of substrate,” Biochem. Biophys. Res. Commun. 29(5), 767–772 (1967).
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Li, L. Z.

L. Z. Li, H. N. Xu, M. Ranji, S. Nioka, and B. Chance, “Mitochondrial redox imaging for cancer diagnostic and therapeutic studies,” J. Innov. Opt. Health Sci. 2(4), 325–341 (2009).
[Crossref] [PubMed]

Lieberman, M.

B. Chance and M. Lieberman, “Intrinsic fluorescence emission from the cornea at low temperatures: evidence of mitochondrial signals and their differing redox states in epithelial and endothelial sides,” Exp. Eye Res. 26(1), 111–117 (1978).
[Crossref] [PubMed]

Lin, H.

E. J. Griffiths, H. Lin, and M. S. Suleiman, “NADH fluorescence in isolated guinea-pig and rat cardiomyocytes exposed to low or high stimulation rates and effect of metabolic inhibition with cyanide,” Biochem. Pharmacol. 56(2), 173–179 (1998).
[Crossref] [PubMed]

Lindqvist, L.

L. Lindqvist, B. Czochralska, and I. Grigorov, “Determination of the mechanism of photoionization of NADH in aqeous solution on laser excitation at 355 nm,” Chem. Phys. Lett. 119(6), 494–498 (1985).
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J. Eng, R. M. Lynch, and R. S. Balaban, “Nicotinamide adenine dinucleotide fluorescence spectroscopy and imaging of isolated cardiac myocytes,” Biophys. J. 55(4), 621–630 (1989).
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P. K. Hammen, A. Allali-Hassani, K. Hallenga, T. D. Hurley, and H. Weiner, “Multiple conformations of NAD and NADH when bound to human cytosolic and mitochondrial aldehyde dehydrogenase,” Biochemistry 41(22), 7156–7168 (2002).
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M. E. Gosnell, A. G. Anwer, J. C. Cassano, C. M. Sue, and E. M. Goldys, “Functional hyperspectral imaging captures subtle details of cell metabolism in olfactory neurosphere cells, disease-specific models of neurodegenerative disorders,” Biochim. Biophys. Acta 1863(1), 56–63 (2016).
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J. Eng, R. M. Lynch, and R. S. Balaban, “Nicotinamide adenine dinucleotide fluorescence spectroscopy and imaging of isolated cardiac myocytes,” Biophys. J. 55(4), 621–630 (1989).
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W. Zeng, P. Liu, W. Pan, S. R. Singh, and Y. Wei, “Hypoxia and hypoxia inducible factors in tumor metabolism,” Cancer Lett. 356(22 Pt A), 263–267 (2015).
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J. P. Brennan, R. G. Berry, M. Baghai, M. R. Duchen, and M. J. Shattock, “FCCP is cardioprotective at concentrations that cause mitochondrial oxidation without detectable depolarisation,” Cardiovasc. Res. 72(2), 322–330 (2006).
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C. Stringari, H. Wang, M. Geyfman, V. Crosignani, V. Kumar, J. S. Takahashi, B. Andersen, and E. Gratton, “In vivo single-cell detection of metabolic oscillations in stem cells,” Cell Reports 10(1), 1–7 (2015).
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J. M. Nascimento and J. M. Bioucas-Dias, “Hyperspectral unmixing based on mixtures of Dirichlet components,” IEEE Trans. Geosc Remot. Sens. 50(3), 863–878 (2012).
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J. Biomed. Opt. (1)

M. C. Skala, K. M. Riching, D. K. Bird, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, P. J. Keely, and N. Ramanujam, “In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia,” J. Biomed. Opt. 12(2), 024014 (2007).
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J. Innov. Opt. Health Sci. (1)

L. Z. Li, H. N. Xu, M. Ranji, S. Nioka, and B. Chance, “Mitochondrial redox imaging for cancer diagnostic and therapeutic studies,” J. Innov. Opt. Health Sci. 2(4), 325–341 (2009).
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K. J. Buckler and R. D. Vaughan-Jones, “Effects of mitochondrial uncouplers on intracellular calcium, pH and membrane potential in rat carotid body type I cells,” J. Physiol. 513(3), 819–833 (1998).
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Figures (5)

Fig. 1
Fig. 1

(a) Excitation-emission matrices (EEM) of the 50 µM NADH solution (b) Peak fluorescence intensity of free NADH and NADPH versus FCCP concentration(10 −5000 µM). Peak fluorescence intensity values for free NADH (black square), free NADPH (red circle), bound NADH (blue triangle) and bound NADPH (magenta triangle) are, respectively, 534, 352, 306 and 626. These data points could not be presented in Fig. 1(b) due to the log scale used in the plot.

Fig. 2
Fig. 2

Oxidation of NADH by FCCP [32].

Fig. 3
Fig. 3

Autofluorescence intensity (excitation at 360 ± 5 nm and emission at 460 ± 5 nm) of control (FCCP = 0) and FCCP -treated HeLa cells.

Fig. 4
Fig. 4

(a) Variation of NAD and NADH levels as a function of FCCP concentration, (b) Variation of NADP and NADPH as a function of FCCP concentration (c) variation of the ratios NAD/NADH and NADP/NADPH as a function of FCCP concentration.

Fig. 5
Fig. 5

(a) Data simplex obtained in unsupervised unmixing of hyperspectral images of HeLa cells exposed to FCCP concentration (50-1000 µM). All images are analysed together. Gray points represent the image pixels, red squares represent the reference spectra, the location of vertices indicates the endmember spectra. The lines mark the sides of the simplex, the axes represent the top 2 PCA components; (b) The results of mean cellular abundance of free NAD(P)H show that FCCP quenches its fluorescence.(c) Mean cellular abundance of bound NADH also shows FCCP quenching. Data for all cells are represented by box plots [37, 38].

Tables (2)

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Table 1 Trypan blue test and percentage viability after treatment with FCCP

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Table 2 Spectral channel specifications for hyperspectral imaging

Equations (4)

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0 C jk 1
k=1 D C jk =1
I j ( λ )=  k=1 D C jk E k ( λ )
I j ( λ )=  k=1 D C jk E k ( λ )+N

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