Home LiteratureArticle Details
PMID: 18832378 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Selective actions of mitochondrial fission/fusion genes on metabolism-secretion coupling in insulin-releasing cells.

The Journal of biological chemistry ·Vol. 283 ·No. 48 ·2008-11-28 ·Pages 33347-56

Park KS, Wiederkehr A, Kirkpatrick C, Mattenberger Y, Martinou JC, Marchetti P, Demaurex N, Wollheim CB

Abstract

Mitochondria form filamentous networks that undergo continuous fission/fusion. In the pancreatic beta-cells, mitochondria are essential for the transduction of signals linking nutrient metabolism to insulin granule exocytosis. Here we have studied mitochondrial networks in the insulinoma cell line INS-1E, primary rat and human beta-cells. We have further investigated the impact of mitochondrial fission/fusion on metabolism-secretion coupling in INS-1E cells. Overexpression of hFis1 caused dramatic mitochondrial fragmentation, whereas Mfn1 evoked hyperfusion and the aggregation of mitochondria. Cells overexpressing hFis1 or Mfn1 showed reduced mitochondrial volume, lowered cellular ATP levels, and as a consequence, impaired glucose-stimulated insulin secretion. Decreased mitochondrial ATP generation was partially compensated for by enhanced glycolysis as indicated by increased lactate production in these cells. Dominant-negative Mfn1 elicited mitochondrial shortening and fragmentation of INS-1E cell mitochondria, similar to hFis1. However, the mitochondrial volume, cytosolic ATP levels, and glucose-stimulated insulin secretion were little affected. We conclude that mitochondrial fragmentation per se does not impair metabolism-secretion coupling. Through their impact on mitochondrial bioenergetics and distribution, hFis1 and Mfn1 activities influence mitochondrial signal generation thereby insulin exocytosis.

MeSH Terms
Adenosine Triphosphate/genetics,metabolism Animals Cell Line, Tumor Exocytosis/physiology GTP Phosphohydrolases/genetics,metabolism Glucose/genetics,metabolism Humans Insulin/genetics,metabolism Insulin Secretion Insulin-Secreting Cells/cytology,metabolism Membrane Fusion/physiology Membrane Proteins/genetics,metabolism Membrane Transport Proteins/genetics,metabolism Mitochondria/genetics,metabolism Mitochondrial Membrane Transport Proteins Mitochondrial Proteins/genetics,metabolism Rats Rats, Wistar Secretory Vesicles/genetics,metabolism Signal Transduction/physiology
Chemicals
FIS1 protein, human Fis1 protein, rat Insulin Membrane Proteins Membrane Transport Proteins Mfn1 protein, rat Mitochondrial Membrane Transport Proteins Mitochondrial Proteins Adenosine Triphosphate GTP Phosphohydrolases Mfn1 protein, human Glucose
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Park Kyu-Sang
Department of Cell Physiology and Metabolism, University of Geneva, CH-1211, Geneva 4, Switzerland.
Wiederkehr Andreas
Kirkpatrick Clare
Mattenberger Yves
Martinou Jean-Claude
Marchetti Piero
Demaurex Nicolas
Wollheim Claes B
References (47)
47 references, click to expand
  1. Charcot-Marie-Tooth disease associated with Type 2 diabetes mellitus.
    Diabet Med. 2001 Aug;18(8):685-6 PMID: 11553211
  2. High levels of Fis1, a pro-fission mitochondrial protein, trigger autophagy.
    Biochim Biophys Acta. 2008 Jul-Aug;1777(7-8):860-6 PMID: 18515060
  3. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes.
    Diabetes. 2002 Oct;51(10):2944-50 PMID: 12351431
  4. Switch to anaerobic glucose metabolism with NADH accumulation in the beta-cell model of mitochondrial diabetes. Characteristics of betaHC9 cells deficient in mitochondrial DNA transcription.
    J Biol Chem. 2002 Nov 1;277(44):41817-26 PMID: 12169697
  5. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development.
    J Cell Biol. 2003 Jan 20;160(2):189-200 PMID: 12527753
  6. Visualizing superoxide production in normal and diabetic rat islets of Langerhans.
    J Biol Chem. 2003 Mar 14;278(11):9796-801 PMID: 12514170
  7. Islet beta-cell secretion determines glucagon release from neighbouring alpha-cells.
    Nat Cell Biol. 2003 Apr;5(4):330-5 PMID: 12640462
  8. Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity.
    J Biol Chem. 2003 May 9;278(19):17190-7 PMID: 12598526
  9. Mitofusin-1 protein is a generally expressed mediator of mitochondrial fusion in mammalian cells.
    J Cell Sci. 2003 Jul 1;116(Pt 13):2763-74 PMID: 12759376
  10. The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1.
    Mol Cell Biol. 2003 Aug;23(15):5409-20 PMID: 12861026
  11. hFis1, a novel component of the mammalian mitochondrial fission machinery.
    J Biol Chem. 2003 Sep 19;278(38):36373-9 PMID: 12783892
  12. Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency.
    Nat Genet. 2003 Dec;35(4):367-71 PMID: 14625552
  13. Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects.
    Diabetes. 2004 Mar;53(3):624-32 PMID: 14988246
  14. Overexpression of Bcl-x(L) in beta-cells prevents cell death but impairs mitochondrial signal for insulin secretion.
    Am J Physiol Endocrinol Metab. 2000 Feb;278(2):E340-51 PMID: 10662719
  15. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells.
    Mol Biol Cell. 2001 Aug;12(8):2245-56 PMID: 11514614
  16. Levels of human Fis1 at the mitochondrial outer membrane regulate mitochondrial morphology.
    J Cell Sci. 2004 Mar 1;117(Pt 7):1201-10 PMID: 14996942
  17. Synaptotagmin V and IX isoforms control Ca2+ -dependent insulin exocytosis.
    J Cell Sci. 2004 Jul 1;117(Pt 15):3119-27 PMID: 15190121
  18. Expanded dynamic range of fluorescent indicators for Ca(2+) by circularly permuted yellow fluorescent proteins.
    Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10554-9 PMID: 15247428
  19. Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis.
    Mol Biol Cell. 2004 Nov;15(11):5001-11 PMID: 15356267
  20. Islet cell metabolism is reflected by the MTT (tetrazolium) colorimetric assay.
    Diabetologia. 1992 May;35(5):482-5 PMID: 1387858
  21. Metabolic fate of glucose in purified islet cells. Glucose-regulated anaplerosis in beta cells.
    J Biol Chem. 1997 Jul 25;272(30):18572-9 PMID: 9228023
  22. Effects of depletion of mitochondrial DNA in metabolism secretion coupling in INS-1 cells.
    Diabetes. 1998 Mar;47(3):374-80 PMID: 9519742
  23. Desensitization of mitochondrial Ca2+ and insulin secretion responses in the beta cell.
    J Biol Chem. 1998 Aug 14;273(33):20770-8 PMID: 9694821
  24. Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity.
    J Cell Sci. 2004 Dec 15;117(Pt 26):6535-46 PMID: 15572413
  25. The diabetes-linked transcription factor PAX4 promotes {beta}-cell proliferation and survival in rat and human islets.
    J Cell Biol. 2004 Dec 20;167(6):1123-35 PMID: 15596543
  26. Functional and molecular defects of pancreatic islets in human type 2 diabetes.
    Diabetes. 2005 Mar;54(3):727-35 PMID: 15734849
  27. Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients.
    Diabetologia. 2005 Feb;48(2):282-9 PMID: 15654602
  28. Disruption of fusion results in mitochondrial heterogeneity and dysfunction.
    J Biol Chem. 2005 Jul 15;280(28):26185-92 PMID: 15899901
  29. Molecular mechanisms of mitochondrial diabetes (MIDD).
    Ann Med. 2005;37(3):213-21 PMID: 16019720
  30. Subplasmalemmal mitochondria modulate the activity of plasma membrane Ca2+-ATPases.
    J Biol Chem. 2005 Dec 30;280(52):43198-208 PMID: 16216868
  31. A large family with Charcot-Marie-Tooth Type 1a and Type 2 diabetes mellitus.
    Int J Neurosci. 2006 Feb;116(2):103-14 PMID: 16393877
  32. Minireview: implication of mitochondria in insulin secretion and action.
    Endocrinology. 2006 Jun;147(6):2643-9 PMID: 16556766
  33. Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons.
    EMBO J. 2006 Aug 23;25(16):3900-11 PMID: 16874299
  34. Inhibition of Ca2+ influx is required for mitochondrial reactive oxygen species-induced endoplasmic reticulum Ca2+ depletion and cell death in leukemia cells.
    Mol Pharmacol. 2006 Oct;70(4):1424-34 PMID: 16849592
  35. Inhibiting the mitochondrial fission machinery does not prevent Bax/Bak-dependent apoptosis.
    Mol Cell Biol. 2006 Oct;26(20):7397-408 PMID: 17015472
  36. Mitochondrial fusion and fission in mammals.
    Annu Rev Cell Dev Biol. 2006;22:79-99 PMID: 16704336
  37. The mitochondrial fission protein hFis1 requires the endoplasmic reticulum gateway to induce apoptosis.
    Mol Biol Cell. 2006 Nov;17(11):4593-605 PMID: 16914522
  38. Mitochondrial bioenergetics and structural network organization.
    J Cell Sci. 2007 Mar 1;120(Pt 5):838-48 PMID: 17298981
  39. Selective degradation of mitochondria by mitophagy.
    Arch Biochem Biophys. 2007 Jun 15;462(2):245-53 PMID: 17475204
  40. Mitochondrial fission and fusion mediators, hFis1 and OPA1, modulate cellular senescence.
    J Biol Chem. 2007 Aug 3;282(31):22977-83 PMID: 17545159
  41. beta-Cell mitochondria exhibit membrane potential heterogeneity that can be altered by stimulatory or toxic fuel levels.
    Diabetes. 2007 Oct;56(10):2569-78 PMID: 17686943
  42. Functions and dysfunctions of mitochondrial dynamics.
    Nat Rev Mol Cell Biol. 2007 Nov;8(11):870-9 PMID: 17928812
  43. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy.
    EMBO J. 2008 Jan 23;27(2):433-46 PMID: 18200046
  44. Expedited approaches to whole cell electron tomography and organelle mark-up in situ in high-pressure frozen pancreatic islets.
    J Struct Biol. 2008 Mar;161(3):298-313 PMID: 18069000
  45. Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation.
    Diabet Med. 2008 Apr;25(4):383-99 PMID: 18294221
  46. Impact of mitochondrial calcium on the coupling of metabolism to insulin secretion in the pancreatic beta-cell.
    Cell Calcium. 2008 Jul;44(1):64-76 PMID: 18191448
  47. Mitochondrial function in normal and diabetic beta-cells.
    Nature. 2001 Dec 13;414(6865):807-12 PMID: 11742413
Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M806251200
Published
2008-11-28
Epub
2008-00-02
Pages
33347-56
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2662262
Subset
IM
External Links
PubMed source DOI: 10.1074/jbc.M806251200 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2