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Intracellular Ca 2+ Increases the Mitochondrial NADH Concentration During Elevated Work in Intact Cardiac Muscle
Abstract
It is not clear how mitochondrial energy production is regulated in intact tissue when energy consumption suddenly changes. Whereas mitochondrial [NADH] ([NADH] m ) may regulate cellular respiration rate and energetic state, it is not clear how [NADH] m itself is controlled during increased work in vivo. We have varied work and [Ca 2+ ] in intact cardiac muscle while assessing [NADH] m using fluorescence spectroscopy. When increased work was accompanied by increasing average [Ca 2+ ] c (by increasing [Ca 2+ ] o or pacing frequency), [NADH] m initially fell and subsequently recovered to a new steady state level. Upon reduction of work, [NADH] m overshot and then returned to control levels. In contrast, when work was increased without increasing average [Ca 2+ ] c (by increasing sarcomere length), [NADH] m fell similarly, but no recovery or overshoot was observed. This Ca 2+ -dependent recovery and overshoot may be attributed to Ca 2+ -dependent stimulation of mitochondrial dehydrogenases. We conclude that the immediate initial increase in respiration rate upon elevation of work is not activated by increased [NADH] m (since [NADH] m rapidly fell) or by [Ca 2+ ] c (since work could also be increased at constant [Ca 2+ ] c ). However, during sustained high work, a Ca 2+ -dependent mechanism causes slow recovery of [NADH] m toward control values. This demonstrates a Ca 2+ -dependent feed-forward control mechanism of cellular energetics in cardiac muscle during increased work.
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“A small class of “uncoupling” proteins, called UCPs 1–4, are believed to induce an inward proton “leak” in charged mitochondria (49, 55, 176, 300).”
From Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function (2009) · cites this paper as [49]
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“Direct experimental evidence that cytosolic Ca2+ follows the work level of the heart has been provided by many investigators in the intact heart[27,28,49,81,87,128,142] and cells or trabeculae[27,28,51,94] [2,12,44].”
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The machinery of local Ca2+ signalling between sarco‐endoplasmic reticulum and mitochondria
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“…of IP×R- and RyR-driven [Ca¥]m signals has been shown in the control of mitochondrial energy metabolism (McCormack et al. 1990; Pralong et al. 1994; Hajn oczky et al. 1995; Rutter et al. 1996; Brandes & Bers, 1997; Roh acs et al. 1997; RobbGaspers et al. 1998a,b; Jouaville et al. 1999).”
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PUFA and aging modulate cardiac mitochondrial membrane lipid composition and Ca2+activation of PDH
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“…[NADH]m and average [Ca2 ]c increased when the workload was increased by increased pacing frequency (Brandes and Bers, 1996; Brandes et al., 1998), but [NADH]m did not increase when the workload was increased by stretching the muscle (no expected increase in [Ca2 ]c) (Brandes and Bers, 1997).”
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“Nonetheless, data obtained on isolated rat ventricular trabeculae indicate that with a sudden increase in stimulation frequency (3 Hz from rest) or extracellular [Ca], there was a transient decrease in mitochondrial NADH ([NADH]m), consistent with NADH production not keeping up with the increased ATP and NADH consumpt…”
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“Indeed, Brandes & Bers (1997) recently demonstrated [Ca¥]c-dependent stimulation of mitochondrial NADH production upon changes in work in intact ventricular muscle which has temporal delays consistent with slow mitochondrial Ca¥ uptake and extrusion.”
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“malate dehydrogenases) required for producing NADH (the main electron donor for ATP in the respiratory chain) and for regenerating NADPH (tomaintain the antioxidative capacity of mitochondrial matrix enzymes) [9].”
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“Accordingly, diminished mitochondrial Ca 2+ uptake oxidizes NADH and FADH 2 (refs.”
InfluentialLi, Q., Pogwizd, S. M., Prabhu, S. D., & Zhou, L. (2014) · PLoS ONE · doi:10.1371/journal.pone.0093928 · Cited by 53
“In cardiomyocyte, mitochondrial energetics largely relies on mitochondrial Ca retention and NADH homeostasis mediated by that Ca retention, especially during the transition of increasing energy demand [38,40,41].”
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Self-citationWüst, R. C. I., de Vries, H. J., Wintjes, L. T., Rodenburg, R. J., Niessen, H. W. M., & Stienen, G. J. M. (2016) · Cardiovascular Research · doi:10.1093/cvr/cvw176 · Cited by 53
“These findings are different from those of Brandes and Bers (1997), who observed a linear relationship between NAD(P)H amplitude and workload when sarcomere length and extracellular Ca2+ concentration were varied.(41) However, it should be noted that they studied the transient after changes in Ca2+ concentration which…”
ResultJo, H., Noma, A., & Matsuoka, S. (2006) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2005.12.012 · Cited by 50
CaMKII does not control mitochondrial Ca2+ uptake in cardiac myocytes
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“As demonstrated previously, the increase of ADP flux to mitochondria associated with this workload transition accelerates electron flow along the ETC, thereby inducing a mild and transient oxidation of the NAD(P)H/NAD(P)+ and FADH2/FAD redox states and the NAD(P)H/FAD ratio, a sensitive index of mitochondrial redox st…”
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Analysis of the Mechanisms of Mitochondrial NADH Regulation in Cardiac Trabeculae
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“8 and Brandes and Bers, 1997).”
BackgroundMethodResultInfluentialSelf-citationMitofusin 2 Is Essential for IP3-Mediated SR/Mitochondria Metabolic Feedback in Ventricular Myocytes
Seidlmayer, L. K., Mages, C., Berbner, A., Eder-Negrin, P., Arias-Loza, P.-A., Kaspar, M., Song, M., Dorn, G. W., Kohlhaas, M., Frantz, S., et al. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00733 · Cited by 44
“The latter finding agrees with previous studies showing that sudden increase in work load causes a decrease in mitochondrial NADH (and presumably ATP levels), which recovered slowly over the time in a Ca2+-dependent manner (Brandes and Bers, 1997).”
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“Furthermore, mitochondrial metabolism can be increased without the associated increase in NADH levels expected to result from activation of mitochondrial dehydrogenases (Wan et al., 1993; White and Wittenberg, 1995; Brandes and Bers, 1997).”
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“We previously observed, in a mouse model of pressure overload, that the increased cardiac workload causes the mismatch between high NADH oxidation and inadequate mitochondrial matrix Ca2+ dependent stimulation of the Krebs cycle [96].”
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“…stimulation produced greater m depolarization and greater elevation of cytosolic [Ca2+] in the presence of amytal. modest (e.g. 700 nm in heart, Brandes & Bers, 1997, 2002; Jo et al. 2006) than in motor terminals, where stimulation-induced elevations of mitochondrial [Ca2+] can be greater and…”
BackgroundMitochondrial Ca2+ Signaling and Cardiac Apoptosis
Pacher, P., Csordás, G., & Hajnóczky, G. (2001) · Neurosignals · doi:10.1159/000046888 · Cited by 37
Haumann, J., Dash, R. K., Stowe, D. F., Boelens, A. D., Beard, D. A., & Camara, A. K. S. (2010) · Biophysical Journal · doi:10.1016/j.bpj.2010.04.069 · Cited by 36
van Beek, H., Tian, X., Zuurbier, C. J., de Groot, B., van Echteld, C. J. A., Eijgelshoven, M. H. J., & Hak, J. B. (1998) · Springer eBooks · doi:10.1007/978-1-4615-5653-4_21 · Cited by 34
Brandes, R. P., Maier, L. S., & Bers, D. M. (1998) · Circulation Research · doi:10.1161/01.res.82.11.1189 · Cited by 33
Self-citationKorzeniewski, B. (2016) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2016.12.001 · Cited by 33
“, Regulation of oxidative computer modeling, Progress in Biophysics and Molecular Biology (2016 NADH overshoot (‘off-overshoot’) was observed (Brandes and Bers, 1997).”
BackgroundMethodInfluentialMitochondrial calcium signaling and redox homeostasis in cardiac health and disease
Popoiu, T.-A., Maack, C., & Bertero, E. (2023) · Frontiers in Molecular Medicine · doi:10.3389/fmmed.2023.1235188 · Cited by 36
“Ca 2+ operates as a second messenger to adjust the rate of mitochondrial oxidative metabolism according to the energy requirements of cardiac myocytes (McCormack and Denton, 1993; Brandes and Bers, 1997).”
BackgroundZuurbier, C. J., & van Beek, H. (1997) · Circulation Research · doi:10.1161/01.res.81.1.69 · Cited by 30
Kohlhaas, M., & Maack, C. (2011) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2012.03.002 · Cited by 29
Control and Regulation of Integrated Mitochondrial Function in Metabolic and Transport Networks
Cortassa, S. C., O'Rourke, B. P., Winslow, R. L., & Aon, M. A. (2009) · International Journal of Molecular Sciences · doi:10.3390/ijms10041500 · Cited by 27
Korzeniewski, B. (2006) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00004.2006 · Cited by 25
“This delay may be due to the transport of calcium through the inner mitochondrial membrane (2, 5) and/or to the kinetics of the activation/inactivation of TCA cycle and oxidative phosphorylation enzymes (16, 20).”
BackgroundMethodInfluentialCardiac Involvement in Mitochondrial Disorders
Popoiu, T.-A., Dudek, J., Maack, C., & Bertero, E. (2023) · Current Heart Failure Reports · doi:10.1007/s11897-023-00592-3 · Cited by 29
van Beek, H., Tian, X., Zuurbier, C. J., de Groot, B., van Echteld, C. J. A., Eijgelshoven, M. H. J., & Hak, J. B. (1998) · Molecular and Cellular Biochemistry · doi:10.1023/a:1006817215408 · Cited by 24
“Indeed, in several studies it was found that mitochondrial NADH fluorescence decreases when cardiac contraction and O 2 consumption was stimulated [49–51].”
BackgroundInfluentialHaumann, J., Camara, A. K. S., Gadicherla, A. K., Navarro, C. D., Boelens, A. D., Blomeyer, C. A., Dash, R. K., Boswell, M. R., Kwok, W., & Stowe, D. F. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2018.01914 · Cited by 23
Román, B., Mastoor, Y., Zhang, Y., Gross, D., Springer, D., Liu, C., Glancy, B. C., & Murphy, E. (2023) · The Journal of Physiology · doi:10.1113/jp284894 · Cited by 25
“The isolated muscle fibres from WT mice did not show any change in NADH after stimulation, consistent with previous studies (Brandes & Bers, 1997; Liu & O’Rourke, 2008).”
ResultZhou, L., Cabrera, M. E., Huang, H., Yuan, C. L., Duda, M. K., Sharma, N., Bian, F., & Stanley, W. C. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.123828 · Cited by 22
“It was proposed previously that in isolated trabeculae, the activation of the citric acid cycle dehydrogenases during rest to work transitions is not instantaneous, but occurs with some delay caused by calcium uptake by mitochondria (Brandes & Bers, 1997; Cortassa et al. 2003).”
BackgroundKohlhaas, M., Nickel, A. G., Bergem, S., Casadei, B., Laufs, U., & Maack, C. (2017) · The Journal of Physiology · doi:10.1113/jp273750 · Cited by 22
“Thus, during β-adrenergic stimulation, the complementary control of respiration and Krebs cycle activity by ADP and Ca2+ maintains stable ATP/ADP and NADH/NAD+ ratios (Maack et al. 2006; Balaban, 2009).”
BackgroundBeat-to-beat dynamic regulation of intracellular pH in cardiomyocytes
Lyu, Y., Thai, P. N., Ren, L., Timofeyev, V., Jian, Z., Park, S., Ginsburg, K. S., Overton, J. L., Bossuyt, J., Bers, D. M., et al. (2021) · iScience · doi:10.1016/j.isci.2021.103624 · Cited by 19
“Hence, the timeaveraged sarcomere lengths reflect the averaged force, an index of ATP consumption rate (Brandes and Bers, 1996, 1997).”
BackgroundSelf-citationOxidative stress in ageing and disease development studied by FT-IR spectroscopy
Anastassopoulou, J. D., Kyriakidou, M., Kyriazis, S., Mavrogenis, A. F., Mamareli, V., Mamarelis, I., Petra, M., Malesiou, E., Kotoulas, C., Kolovou, P., et al. (2017) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2017.11.009 · Cited by 19
Barbey, O., Pierre, S. V., Duran, M., Sennoune, S. R., Lévy, S., & Maixent, J. M. (2000) · Journal of Cardiovascular Electrophysiology · doi:10.1111/j.1540-8167.2000.tb00339.x · Cited by 19
Mitochondrial junctions with cellular organelles: Ca2+ signalling perspective
Tepikin, A. V. (2018) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-018-2179-z · Cited by 19
Increased Energy Demand during Adrenergic Receptor Stimulation Contributes to Ca 2+ Wave Generation
Bovo, E., Mazurek, S. R., de Tombe, P. P., & Zima, A. V. (2015) · Biophysical Journal · doi:10.1016/j.bpj.2015.09.002 · Cited by 16
Lima, P. R. D. V., Ronconi, K. S., Morra, E. A., Rodrigues, P. L., Ávila, R. A., Merlo, E., Graceli, J. B., Simões, M. R., Stefanon, I., & Júnior, R. F. R. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1206387 · Cited by 15
“Efficient matching of energy production and consumption is crucial for beatto-beat adaptation to changes in cardiac workload and involves important molecules and ions such as ADP and Ca (38, 39).”
BackgroundDigitalis and Na/Ca exchange: Old dog learns new mitochondrial tricks
Bers, D. M. (2010) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2010.08.004 · Cited by 14
Self-citationVisualization of Dynamic Mitochondrial Calcium Fluxes in Isolated Cardiomyocytes
Krstic, A. M., Power, A., & Ward, M. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2021.808798 · Cited by 13
Healthy versus sick myocytes: metabolism, structure and function
Ferrari, R. (2002) · European Heart Journal Supplements · doi:10.1016/s1520-765x(02)90084-2 · Cited by 13
“ventricular myocytes, most calcium is removed by the SR calcium pump (SERCA2a) and partly, to a variable extent depending on the species studied[8,10–13], by the sodium–calcium exchanger in the sarcolemma.”
BackgroundKawamura, Y., Ishiwata, T., Takizawa, M., Ishida, H., Asano, Y., & Nonoyama, S. (2010) · Circulation Journal · doi:10.1253/circj.cj-09-0793 · Cited by 13
Impaired Atrial Mitochondrial Calcium Handling in Patients With Atrial Fibrillation
Pronto, J. R. D., Mason, F. E., Rog‐Zielinska, E. A., Fakuade, F. E., Bülow, D., Tóth, M., Machwart, K., Brandes, P., Wiedmann, F., Kohlhaas, M., et al. (2025) · Circulation Research · doi:10.1161/circresaha.124.325658 · Cited by 12
Implications of SGLT Inhibition on Redox Signalling in Atrial Fibrillation
Bode, D., Semmler, L., Oeing, C. U., Alogna, A., Schiattarella, G. G., Pieske, B. M., Heinzel, F. R., & Hohendanner, F. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115937 · Cited by 11
“, pyruvate-, α-ketoglutarateand isocitrate dehydrogenase) and elevates the availability of NADH and FADH2 [96,97].”
BackgroundScaduto, R. C., & Grotyohann, L. W. (2000) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.2000.279.4.h1839 · Cited by 11
Regulation of Cardiac Energetics: Role of Redox State and Cellular Compartmentation during Ischemia
Cabrera, M. E., Zhou, L., Stanley, W. C., & Saidel, G. M. (2005) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1341.023 · Cited by 11
Metadata
- Authors
- Brandes, R., & Bers, D. M.
- Affiliations
- the Department of Physiology, Loyola University Chicago, School of Medicine, Maywood, Ill. E-mail rbrande@luc.edu
- Loyola University Chicago (US)
- ORCID
- Bers, Donald M.
- Venue
- Circulation Research
- Published
- 1997-01
- Volume
- 80
- Issue
- 1
- Pages
- 82-87
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W1979697035
- Cited by
- 130
- References
- 32
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 2 · 2023: 5 · 2022: 2 · 2021: 4 · 2020: 2 · 2019: 4 · 2018: 6 · 2017: 5 · 2016: 5 · 2015: 8 · 2014: 3 · 2013: 5 · 2012: 4
- FWCI
- 2.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01hl052478-05)
- National Heart, Lung, and Blood Institute (HL52478, HL30077)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- intracellular calcium, mitochondrial NADH, myocardium, mitochondrial respiration, energy metabolism, sarcomere length, pacing rate, mitochondrial dehydrogenases, feedforward control, NADH fluorescence
- MeSH terms
- Animals, Calcium, Energy Metabolism, Intracellular Membranes, Kinetics, Male, Mitochondria, NAD, Osmolar Concentration, Papillary Muscles, Rats, Inbred Strains, Temperature, Rats
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