Evidence map›Paper›PMID 24634818›Full record

ArticleMolecular metabolism2014

Opening of the mitochondrial permeability transition pore links mitochondrial dysfunction to insulin resistance in skeletal muscle.

E P Taddeo, R C Laker, D S Breen, Y N Akhtar, B M Kenwood, J A Liao, M Zhang, D J Fazakerley, J L Tomsig, T E Harris and 9 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular metabolism, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers.

0numbers the graph read from it
0cells of the map it votes in
68citing papers in PubMed
4.3field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

68 citing papers in PubMed, 116 citations in OpenAlex.

  1. Trial
  2. Review
  3. Article
  4. Article
  5. Review
  6. Review
  7. Article
  8. Review
  9. Review
  10. Article
  11. Review
  12. Article
  13. Review
  14. Article
  15. Article
  16. Article
  17. Annals of translational medicine · 2023
    Article
  18. Mitochondrial Permeability Transition in Stem Cells, Development, and Disease.Advances in experimental medicine and biology · 2023
    Review
  19. Article
  20. Article

8 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

19 authors at 5 institutions in 3 countries.

E P TaddeoDepartment of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
R C LakerDepartment of Medicine, University of Virginia, Charlottesville, VA 22908, USA ; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
D S BreenDepartment of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
Y N AkhtarDepartment of Medicine, University of Virginia, Charlottesville, VA 22908, USA ; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
B M KenwoodDepartment of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
J A LiaoDepartment of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
M ZhangDepartment of Medicine, University of Virginia, Charlottesville, VA 22908, USA ; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
D J FazakerleyDiabetes and Obesity Program, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia.
J L TomsigDepartment of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
T E HarrisDepartment of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
S R KellerDepartment of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
J D ChowDepartment of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
K R LynchDepartment of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA ; Emily Couric Clinical Cancer Center, University of Virginia, Charlottesville, VA 22908, USA.
M ChokkiTeijin Pharma Limited, 4-3-2, Asahigaoka, Hino, Tokyo 191-8512, Japan.
J D MolkentinDepartment of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Howard Hughes Medical Institute, Cincinnati, OH, USA.
N TurnerDepartment of Pharmacology, University of New South Wales, Sydney, NSW, Australia.
D E JamesDiabetes and Obesity Program, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia ; School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia ; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.
Z YanDepartment of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA ; Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA ; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
K L HoehnDepartment of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA ; Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA ; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA ; Emily Couric Clinical Cancer Center, University of Virginia, Charlottesville, VA 22908, USA.
University of Virginia · USGarvan Institute of Medical Research · AUCincinnati Children's Hospital Medical Center · USTeijin (Japan) · JPUNSW Sydney · AU

Funding

TRAINING IN THE PHARMACOLOGICAL SCIENCEST32GM007055 · NIGMS · UNIVERSITY OF VIRGINIA CHARLOTTESVILLE · PI LYNCH, KEVIN R. · 1985 to 2022
$7.2M
Role of Oxidized neutral lipids in adipocyte functionR01DK101946 · NIDDK · UNIVERSITY OF VIRGINIA · PI HARRIS, THURL E. · 2014 to 2018
$1.7M
NIDDK NIH HHS R01 DK101946NIGMS NIH HHS T32 GM007055
6 · The paper itself

Abstract

Insulin resistance is associated with mitochondrial dysfunction, but the mechanism by which mitochondria inhibit insulin-stimulated glucose uptake into the cytoplasm is unclear. The mitochondrial permeability transition pore (mPTP) is a protein complex that facilitates the exchange of molecules between the mitochondrial matrix and cytoplasm, and opening of the mPTP occurs in response to physiological stressors that are associated with insulin resistance. In this study, we investigated whether mPTP opening provides a link between mitochondrial dysfunction and insulin resistance by inhibiting the mPTP gatekeeper protein cyclophilin D (CypD) in vivo and in vitro. Mice lacking CypD were protected from high fat diet-induced glucose intolerance due to increased glucose uptake in skeletal muscle. The mitochondria in CypD knockout muscle were resistant to diet-induced swelling and had improved calcium retention capacity compared to controls; however, no changes were observed in muscle oxidative damage, insulin signaling, lipotoxic lipid accumulation or mitochondrial bioenergetics. In vitro, we tested 4 models of insulin resistance that are linked to mitochondrial dysfunction in cultured skeletal muscle cells including antimycin A, C2-ceramide, ferutinin, and palmitate. In all models, we observed that pharmacological inhibition of mPTP opening with the CypD inhibitor cyclosporin A was sufficient to prevent insulin resistance at the level of insulin-stimulated GLUT4 translocation to the plasma membrane. The protective effects of mPTP inhibition on insulin sensitivity were associated with improved mitochondrial calcium retention capacity but did not involve changes in insulin signaling both in vitro and in vivo. In sum, these data place the mPTP at a critical intersection between alterations in mitochondrial function and insulin resistance in skeletal muscle.

Indexed as

[3H]-2-DOG, [3H]-2-deoxyglucoseANT, adenine nucleotide translocatorBKA, bongkrekic acidCSA, cyclosporin ACyclophilin DCYPD, cyclophilin DDAG, diacylglycerolETC, electron transport chainFFA, free fatty acidGlucoseHFD, high fat dietHK2, hexokinase 2Insulin resistanceKO, knockoutLFD, low fat dietMCAD, medium chain acyl-CoA dehydrogenaseMHC, myosin heavy chainMIRKO, muscle insulin receptor knockoutMitochondrial dysfunctionMitochondrial permeability transition poreMnSOD, mitochondrial manganese superoxide dismutaseMPTP, mitochondrial permeability transition poreO2•, superoxideOXPHOS, oxidative phosphorylationPDHa, active PDHPDH, pyruvate dehydrogenasePDHt, total PDHPM, plasma membraneRg′, rate of glucose transportSkeletal muscleTBARS, thiobarbituric acid reactive substancesTEM, transmission electron microscopyVDAC, voltage-dependent anion channelWT, wild typeβ-HAD, β-hydroxyacyl-CoA dehydrogenase

Identifiers

PMID24634818
PMCPMC3953683
OpenAlexW2057704034

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.