CoChat
Sign Up
Cited by 81Pancreatic function and diabetesMitochondrial Function and PathologyCalcium signaling and nucleotide metabolism

Frequency-dependent mitochondrial Ca2+ accumulation regulates ATP synthesis in pancreatic β cells

Open access
Tarasov, Andrei I., Semplici, Francesca, Li, Daliang, Rizzuto, Rosario, Ravier, Magalie A., Gilon, Patrick, Rutter, Guy A.·2013·Pflügers Archiv - European Journal of Physiology
DOI 10.1007/s00424-012-1177-9PMC PMC3631125
Open this paper in CoChat — free accountOpen PDF

Abstract

Pancreatic β cells respond to increases in glucose concentration with enhanced metabolism, the closure of ATP-sensitive K(+) channels and electrical spiking. The latter results in oscillatory Ca(2+) influx through voltage-gated Ca(2+) channels and the activation of insulin release. The relationship between changes in cytosolic and mitochondrial free calcium concentration ([Ca(2+)]cyt and [Ca(2+)]mit, respectively) during these cycles is poorly understood. Importantly, the activation of Ca(2+)-sensitive intramitochondrial dehydrogenases, occurring alongside the stimulation of ATP consumption required for Ca(2+) pumping and other processes, may exert complex effects on cytosolic ATP/ADP ratios and hence insulin secretion. To explore the relationship between these parameters in single primary β cells, we have deployed cytosolic (Fura red, Indo1) or green fluorescent protein-based recombinant-targeted (Pericam, 2mt8RP for mitochondria; D4ER for the ER) probes for Ca(2+) and cytosolic ATP/ADP (Perceval) alongside patch-clamp electrophysiology. We demonstrate that: (1) blockade of mitochondrial Ca(2+) uptake by shRNA-mediated silencing of the uniporter MCU attenuates glucose- and essentially blocks tolbutamide-stimulated, insulin secretion; (2) during electrical stimulation, mitochondria decode cytosolic Ca(2+) oscillation frequency as stable increases in [Ca(2+)]mit and cytosolic ATP/ADP; (3) mitochondrial Ca(2+) uptake rates remained constant between individual spikes, arguing against activity-dependent regulation ("plasticity") and (4) the relationship between [Ca(2+)]cyt and [Ca(2+)]mit is essentially unaffected by changes in endoplasmic reticulum Ca(2+) ([Ca(2+)]ER). Our findings thus highlight new aspects of Ca(2+) signalling in β cells of relevance to the actions of both glucose and sulphonylureas.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1007/s00424-012-1177-9

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Ca2+ import into mitochondria is mediated by the mitochondrial Ca2+ uniporter (MCU), and silencing MCU in β-cells reduces the increase in intracellular ATP/ADP produced by glucose.

    “Ca2+ import into the mitochondria is mediated by the mitochondrial Ca2+ uniporter (MCU) and silencing MCU in β-cells reduces the increase in intracellular ATP/ADP produced by glucose (676).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [676]

    The Discussion section, “Role of mitochondrial Ca2+ transport mediated by MCU in the control of insulin secretion” (page not available), identifies MCU as mediating mitochondrial Ca2+ transport and says MCU silencing sharply reduced the second phase of the glucose-induced ATP/ADP increase in β cells. It also says the first-phase ATP increase was unaffected, a qualification missing from the citing sentence. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Initiation of electrical activity is associated with a transient drop in the cytoplasmic ATP/ADP ratio.

    “They show that initiation of electrical activity is associated with a transient drop in the cytoplasmic ATP/ADP ratio (676, 677).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [676]

    The Results section, “Cytosolic ATP/ADP increases are controlled by electrical bursting and [Ca2+]cyt oscillation frequency” (page unavailable), reports a transient drop when bursts were imposed at 4 min−1. The claim omits that frequency condition: imposed oscillations at 1 min−1 had no discernible effect on the cytosolic ATP/ADP ratio. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 53

  1. [1]Ainscow EK Rutter GA Mitochondrial priming modifies Ca2+ oscillations and insulin secretion in pancreatic islets Biochem J 2001 353 175 180 10.1042/0264-6021:3530175 11139378 PMC1221556 · DOI
  2. [2]Ainscow EK Rutter GA Glucose-stimulated oscillations in free cytosolic ATP concentration imaged in single islet β cells: evidence for a Ca2+-dependent mechanism Diabetes 2002 51 S162 S170 10.2337/diabetes.51.2007.S162 11815476 · DOI
  3. [3]Alam MR, Groschner LN, Parichatikanond W, Kuo L, Bondarenko AI, Rost R, Waldeck-Weiermair M, Malli R and Graier WF (2012) Mitochondrial Ca2+ uptake 1 (MICU1) and mitochondrial Ca2+ uniporter (MCU) contribute to metabolism-secretion coupling in clonal pancreatic beta-cells. J Biol Chem 287:34445–34454 PMC3464549 22904319
  4. [4]Ashcroft SJH The beta-cell K-ATP channel J Membrane Biol 2000 176 187 206 10.1007/s002320001095 10931971 · DOI
  5. [5]Baughman JM Perocchi F Girgis HS Plovanich M Belcher-Timme CA Sancak Y Bao XR Strittmatter L Goldberger O Bogorad RL Koteliansky V Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter Nature 2011 476 341 345 10.1038/nature10234 21685886 PMC3486726 · DOI
  6. [6]Berg J Hung YP Yellen G A genetically encoded fluorescent reporter of ATP:ADP ratio Nat Methods 2009 6 161 166 10.1038/nmeth.1288 19122669 PMC2633436 · DOI
  7. [8]Corkey BE Tornheim K Deeney JT Glennon MC Parker JC Matschinsky FM Ruderman NB Prentki M Linked oscillations of free Ca2+ and the ATP/ADP ratio in permeabilized RINm5F insulinoma cells supplemented with a glycolyzing cell-free muscle extract J Biol Chem 1988 263 4254 4258 2831225
  8. [9]Csordas G Hajnoczky G Plasticity of mitochondrial calcium signaling J Biol Chem 2003 278 42273 42282 10.1074/jbc.M305248200 12907683 · DOI
  9. [10]Davidson AM Halestrap AP Inhibition of mitochondrial-matrix inorganic pyrophosphatase by physiological (Ca2+), and its role in the hormonal regulation of mitochondrial matrix volume Biochem J 1989 258 817 821 2543362 PMC1138437
  10. [11]De Stefani D, Raffaello A, Teardo E, Szabo I, Rizzuto R (2011) A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476:336–340 PMC4141877 21685888
  11. [12]Denton RM McCormack JG On the role of the calcium transport cycle in the heart and other mammalian mitochondria FEBS Lett 1980 119 1 8 10.1016/0014-5793(80)80986-0 7000543 · DOI
  12. [13]Detimary P Gilon P Henquin JC Interplay between cytoplasmic Ca2+ and the ATP/ADP ratio: a feedback control mechanism in mouse pancreatic islets Biochem J 1998 333 269 274 9657965 PMC1219582
  13. [14]Diraison F Parton L Ferre P Foufelle F Briscoe CP Leclerc I Rutter GA Over-expression of sterol-regulatory-element-binding protein-1c (SREBP1c) in rat pancreatic islets induces lipogenesis and decreases glucose-stimulated insulin release: modulation by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) Biochem J 2004 378 769 778 10.1042/BJ20031277 14690455 PMC1224038 · DOI
  14. [15]Dolmetsch RE Lewis RS Goodnow CC Healy JI Differential activation of transcription factors induced by Ca2+ response amplitude and duration Nature 1997 386 855 858 10.1038/386855a0 9126747 · DOI
  15. [16]Dolmetsch RE Xu KL Lewis RS Calcium oscillations increase the efficiency and specificity of gene expression Nature 1998 392 933 936 10.1038/31960 9582075 · DOI
  16. [17]Ferrer R Atwater I Omer EM Goncalves AA Croghan PC Rojas E Electrophysiological evidence for the inhibition of potassium permeability in pancreatic beta-cells by glibenclamide Q J Exp Physiol 1984 69 831 839 6096914
  17. [18]Filippin L Abad MC Gastaldello S Magalhaes PJ Sandona D Pozzan T Improved strategies for the delivery of GFP-based Ca2+ sensors into the mitochondrial matrix Cell Calcium 2005 37 129 136 10.1016/j.ceca.2004.08.002 15589993 · DOI
  18. [19]Filippin L Magalhaes PJ Di Benedetto G Colella M Pozzan T Stable interactions between mitochondria and endoplasmic reticulum allow rapid accumulation of calcium in a subpopulation of mitochondria J Biol Chem 2003 278 39224 39234 10.1074/jbc.M302301200 12874292 · DOI
  19. [21]Hajnoczky G Robb-Gaspers LD Seitz MB Thomas AP Decoding of cytosolic calcium oscillations in the mitochondria Cell 1995 82 415 424 10.1016/0092-8674(95)90430-1 7634331 · DOI
  20. [22]Halestrap AP A pore way to die: the role of mitochondria in reperfusion injury and cardioprotection Biochem Soc Trans 2010 38 841 860 10.1042/BST0380841 20658967 · DOI
  21. [23]Henquin JC Regulation of insulin secretion: a matter of phase control and amplitude modulation Diabetologia 2009 52 739 751 10.1007/s00125-009-1314-y 19288076 · DOI
  22. [24]Jouaville LS, Pinton P, Bastianutto C, Rutter GA and Rizzuto R (1999) Regulation of mitochondrial ATP synthesis by calcium: evidence for a long-term metabolic priming. Proc Natl Acad Sci U S A 96:13807–13812 PMC24146 10570154
  23. [25]Kennedy ED Rizzuto R Theler JM Pralong WF Bastianutto C Pozzan T Wollheim CB Glucose-stimulated insulin secretion correlates with changes in mitochondrial and cytosolic Ca2+ in aequorin-expressing INS-1 cells J Clin Invest 1996 98 2524 2538 10.1172/JCI119071 8958215 PMC507710 · DOI
  24. [26]Li D Chen S Bellomo EA Tarasov AI Kaut C Rutter GA Li WH Imaging dynamic insulin release using a fluorescent zinc probe, ZIMIR Proc Natl Acad Sci U S A 2011 108 21063 21068 10.1073/pnas.1109773109 22160693 PMC3248484 · DOI
  25. [27]Lipton SA Rosenberg PA Excitatory amino acids as a final common pathway for neurologic disorders N Engl J Med 1994 330 613 622 10.1056/NEJM199403033300907 7905600 · DOI
  26. [28]Luo J Deng ZL Luo X Tang N Song WX Chen J Sharff KA Luu HH Haydon RC Kinzler KW Vogelstein B A protocol for rapid generation of recombinant adenoviruses using the AdEasy system Nat Protoc 2007 2 1236 1247 10.1038/nprot.2007.135 17546019 · DOI
  27. [29]Maechler P Kennedy ED Wang HY Wollheim CB Desensitization of mitochondrial Ca2+ and insulin secretion responses in the beta cell J Biol Chem 1998 273 20770 20778 10.1074/jbc.273.33.20770 9694821 · DOI
  28. [30]Maechler P Wollheim CB Mitochondrial function in normal and diabetic beta-cells Nature 2001 414 807 812 10.1038/414807a 11742413 · DOI · Paper page
  29. [31]Malaisse WJ Sener JA Herchuelz A Hutton JC Insulin release: the fuel hypothesis Metabolism 1979 28 373 385 10.1016/0026-0495(79)90111-2 36543 · DOI
  30. [32]Manning Fox JE Gyulkhandanyan AV Satin LS Wheeler MB Oscillatory membrane potential response to glucose in islet beta-cells: a comparison of islet-cell electrical activity in mouse and rat Endocrinology 2006 147 4655 4663 10.1210/en.2006-0424 16857746 · DOI · Paper page
  31. [33]Meissner HP (1990) Membrane potential measurements in pancreatic beta cells with intracellular microelectrodes. Methods Enzymol 192:235–246 2074791
  32. [34]O'Rahilly S Turner RC Matthews DR Impaired pulsatile secretion of insulin in relatives of patients with non-insulin-dependent diabetes N Engl J Med 1988 318 1225 1230 10.1056/NEJM198805123181902 3283553 · DOI · Paper page
  33. [35]Palmer AE Jin C Reed JC Tsien RY Bcl-2-mediated alterations in endoplasmic reticulum Ca2+ analyzed with an improved genetically encoded fluorescent sensor Proc Natl Acad Sci U S A 2004 101 17404 17409 10.1073/pnas.0408030101 15585581 PMC535104 · DOI
  34. [36]Perocchi F Gohil VM Girgis HS Bao XR McCombs JE Palmer AE Mootha VK MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake Nature 2010 467 291 296 10.1038/nature09358 20693986 PMC2977980 · DOI
  35. [37]Pinton P Giorgi C Siviero R Zecchini E Rizzuto R Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis Oncogene 2008 27 6407 6418 10.1038/onc.2008.308 18955969 PMC2844952 · DOI
  36. [38]Pralong WF Bartley C Wollheim CB Single islet beta-cell stimulation by nutrients: relationship between pyridine nucleotides, cytosolic Ca2+ and secretion EMBO J 1990 9 53 60 2403930 PMC551629
  37. [39]Pralong WF Spat A Wollheim CB Dynamic pacing of cell metabolism by intercellular Ca2+ transients J Biol Chem 1994 269 27310 27314 7961642
  38. [40]Ravier MA Daro D Roma LP Jonas JC Cheng-Xue R Schuit FC Gilon P Mechanisms of control of the free Ca2+ concentration in the endoplasmic reticulum of mouse pancreatic {beta}-cells: interplay with cell metabolism and [Ca2+]c, and role of SERCA2b and SERCA3 Diabetes 2011 60 2533 2545 10.2337/db10-1543 21885870 PMC3178295 · DOI
  39. [41]Ravier MA Rutter GA Glucose or insulin, but not zinc ions, inhibit glucagon secretion from mouse pancreatic alpha-cells Diabetes 2005 54 1789 1797 10.2337/diabetes.54.6.1789 15919801 · DOI · Paper page
  40. [42]Rutter GA Ca2+-binding to citrate cycle enzymes Int J Biochem 1990 22 1081 1088 10.1016/0020-711X(90)90105-C 2289614 · DOI
  41. [43]Rutter GA Nutrient-secretion coupling in the pancreatic islet β-cell: recent advances Molecular Aspects of Medicine 2001 22 247 284 10.1016/S0098-2997(01)00013-9 11890977 · DOI
  42. [44]Rutter GA Visualising insulin secretion. The Minkowski lecture 2004 Diabetologia 2004 47 1861 1872 10.1007/s00125-004-1541-1 15551048 · DOI
  43. [45]Rutter GA Pralong W-F Wollheim CB Regulation of mitochondrial glycerol phosphate dehydrogenase activity by Ca2+ within electropermeabilized insulin-secreting cells (INS1) Biochimica et Biophysica Acta - Bioenergetics 1992 1175 107 113 10.1016/0167-4889(92)90016-5 1482691 · DOI
  44. [46]Rutter GA Rizzuto R Regulation of mitochondrial metabolism by ER Ca2+ release: an intimate connection Trends Biochem Sci 2000 25 215 221 10.1016/S0968-0004(00)01585-1 10782088 · DOI
  45. [47]Rutter GA Theler J-M Murta M Wollheim CB Pozzan T Rizzuto R Stimulated Ca2+ influx raises mitochondrial free Ca2+ to supramicromolar levels in a pancreatic β-cell line: possible role in glucose and agonist-induced insulin secretion J Biol Chem 1993 268 22385 22390 8226749
  46. [48]Rutter GA Tsuboi T Ravier MA Ca2+ microdomains and the control of insulin secretion Cell Calcium 2006 40 539 551 10.1016/j.ceca.2006.08.015 17030367 · DOI
  47. [50]Sekine N Cirulli V Regazzi R Brown LJ Gine E Tamarit-Rodriguez J Girotti M Marie S MacDonald MJ Wollheim CB Rutter GA Low lactate dehydrogenase and high mitochondrial glycerol phosphate dehydrogenase in pancreatic β-cell Potential role in nutrient sensing. J Biol Chem 1994 269 4895 4902 8106462
  48. [51]Tarasov AI Griffiths EJ Rutter GA Regulation of ATP production by mitochondrial Ca(2+) Cell Calcium 2012 52 28 35 10.1016/j.ceca.2012.03.003 22502861 PMC3396849 · DOI · Paper page
  49. [52]Tarasov AI Nicolson T Riveline JP Taneja TK Baldwin SA Baldwin JM Charpentier G Gautier JF Froguel P Vaxillaire M Rutter GA A rare mutation in ABCC8/SUR1 leading to altered KATP channel activity and {beta}-cell glucose sensing is associated with type 2 diabetes mellitus in adults Diabetes 2008 57 1595 1604 10.2337/db07-1547 18346985 PMC6101196 · DOI
  50. [53]Tarasov AI, Ravier MA, Semplici F, Bellomo EA, Pullen TJ, Gilon P, Sekler I, Rizzuto R, Rutter GA (2012) The mitochondrial Ca2+ uniporter MCU is essential for glucose-induced ATP increases in pancreatic beta-cells. PLoS One 7(7):e39722 PMC3400633 22829870
  51. [54]Whitaker M Calcium signalling in early embryos Philos Trans R Soc Lond B Biol Sci 2008 363 1401 1418 10.1098/rstb.2008.2259 18263556 PMC2610129 · DOI
  52. [55]Wiederkehr A Szanda G Akhmedov D Mataki C Heizmann CW Schoonjans K Pozzan T Spat A Wollheim CB Mitochondrial matrix calcium is an activating signal for hormone secretion Cell Metab 2011 13 601 611 10.1016/j.cmet.2011.03.015 21531342 · DOI
  53. [56]Yingst DR Davis J Schiebinger R Effects of extracellular calcium and potassium on the sodium pump of rat adrenal glomerulosa cells Am J Physiol Cell Physiol 2001 280 C119 C125 11121383

Cited by

Sorted by citations

Authors
Tarasov, A. I., Semplici, F., Li, D., Rizzuto, R., Ravier, M. A., Gilon, P., & Rutter, G. A.
Affiliations
  • Imperial College London (GB)
  • The University of Texas Southwestern Medical Center (US)
  • University of Padua (IT)
  • Centre National de la Recherche Scientifique (FR)
  • UCLouvain (BE)
Corresponding author
Rutter, Guy A.
ORCID
Venue
Pflügers Archiv - European Journal of Physiology
Publisher
Springer Science and Business Media LLC
Published
2012-11-14
Volume
465
Issue
4
Pages
543-554
ISSN
  • 0031-6768 (ISSN-L)
  • 1432-2013
DOI
10.1007/s00424-012-1177-9
PMC
PMC3631125
OpenAlex
W2129483239
Cited by
81
References
3
Citations by year
2026: 2 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 2 · 2021: 8 · 2020: 6 · 2019: 3 · 2018: 8 · 2017: 11 · 2016: 8 · 2015: 4 · 2014: 9 · 2013: 5
FWCI
5.88
Type
journal article
Language
en
Open access
Licence
Locations
  • Pflügers Archiv - European Journal of Physiology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion, cc-by)
Funders
  • Yale University
  • Wellcome Trust (098424, WT098424AIA, 081958, 081958/Z/07/Z)
  • University of Bristol
  • Institut National de la Santé et de la Recherche Médicale
  • Medical Research Council (MR/K001981/1)
  • Biotechnology and Biological Sciences Research Council (BB/J015873/1)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords
pancreatic beta cells, mitochondrial calcium uptake, ATP production, cytosolic calcium oscillations, ATP/ADP ratio, insulin secretion, voltage-gated calcium channels, sulfonylureas, tolbutamide, endoplasmic reticulum calcium, glucose signaling, calcium signaling
MeSH terms
Action Potentials, Adenosine Diphosphate, Adenosine Triphosphate, Animals, Calcium, Cells, Cultured, Cytosol, Endoplasmic Reticulum, Female, Glucose, Insulin, Mitochondria, Calcium Channels, Calcium Signaling, Insulin-Secreting Cells, 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.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review