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Inhibition of insulin/IGF-1 receptor signaling protects from mitochondria-mediated kidney failure

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Inhibition of insulin/IGF-1 receptor signaling protects from mitochondria-mediated kidney failure. / Ising, Christina; Koehler, Sybille; Brähler, Sebastian; Merkwirth, Carsten; Höhne, Martin; Baris, Olivier R; Hagmann, Henning; Kann, Martin; Fabretti, Francesca; Dafinger, Claudia; Bloch, Wilhelm; Schermer, Bernhard; Linkermann, Andreas; Brüning, Jens C; Kurschat, Christine E; Müller, Roman-Ulrich; Wiesner, Rudolf J; Langer, Thomas; Benzing, Thomas; Brinkkoetter, Paul Thomas.

In: EMBO MOL MED, Vol. 7, No. 3, 03.2015, p. 275-87.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Ising, C, Koehler, S, Brähler, S, Merkwirth, C, Höhne, M, Baris, OR, Hagmann, H, Kann, M, Fabretti, F, Dafinger, C, Bloch, W, Schermer, B, Linkermann, A, Brüning, JC, Kurschat, CE, Müller, R-U, Wiesner, RJ, Langer, T, Benzing, T & Brinkkoetter, PT 2015, 'Inhibition of insulin/IGF-1 receptor signaling protects from mitochondria-mediated kidney failure', EMBO MOL MED, vol. 7, no. 3, pp. 275-87. https://doi.org/10.15252/emmm.201404916

APA

Ising, C., Koehler, S., Brähler, S., Merkwirth, C., Höhne, M., Baris, O. R., Hagmann, H., Kann, M., Fabretti, F., Dafinger, C., Bloch, W., Schermer, B., Linkermann, A., Brüning, J. C., Kurschat, C. E., Müller, R-U., Wiesner, R. J., Langer, T., Benzing, T., & Brinkkoetter, P. T. (2015). Inhibition of insulin/IGF-1 receptor signaling protects from mitochondria-mediated kidney failure. EMBO MOL MED, 7(3), 275-87. https://doi.org/10.15252/emmm.201404916

Vancouver

Ising C, Koehler S, Brähler S, Merkwirth C, Höhne M, Baris OR et al. Inhibition of insulin/IGF-1 receptor signaling protects from mitochondria-mediated kidney failure. EMBO MOL MED. 2015 Mar;7(3):275-87. https://doi.org/10.15252/emmm.201404916

Bibtex

@article{d9df3b49ffb74b34bcf87781da080a7d,
title = "Inhibition of insulin/IGF-1 receptor signaling protects from mitochondria-mediated kidney failure",
abstract = "Mitochondrial dysfunction and alterations in energy metabolism have been implicated in a variety of human diseases. Mitochondrial fusion is essential for maintenance of mitochondrial function and requires the prohibitin ring complex subunit prohibitin-2 (PHB2) at the mitochondrial inner membrane. Here, we provide a link between PHB2 deficiency and hyperactive insulin/IGF-1 signaling. Deletion of PHB2 in podocytes of mice, terminally differentiated cells at the kidney filtration barrier, caused progressive proteinuria, kidney failure, and death of the animals and resulted in hyperphosphorylation of S6 ribosomal protein (S6RP), a known mediator of the mTOR signaling pathway. Inhibition of the insulin/IGF-1 signaling system through genetic deletion of the insulin receptor alone or in combination with the IGF-1 receptor or treatment with rapamycin prevented hyperphosphorylation of S6RP without affecting the mitochondrial structural defect, alleviated renal disease, and delayed the onset of kidney failure in PHB2-deficient animals. Evidently, perturbation of insulin/IGF-1 receptor signaling contributes to tissue damage in mitochondrial disease, which may allow therapeutic intervention against a wide spectrum of diseases.",
keywords = "Animals, Gene Deletion, Insulin/metabolism, Mice, Inbred C57BL, Mitochondria/metabolism, Phosphorylation, Prohibitins, Protein Processing, Post-Translational, Receptor, IGF Type 1/metabolism, Receptor, Insulin/genetics, Renal Insufficiency, Repressor Proteins/genetics, Ribosomal Protein S6/metabolism, Signal Transduction",
author = "Christina Ising and Sybille Koehler and Sebastian Br{\"a}hler and Carsten Merkwirth and Martin H{\"o}hne and Baris, {Olivier R} and Henning Hagmann and Martin Kann and Francesca Fabretti and Claudia Dafinger and Wilhelm Bloch and Bernhard Schermer and Andreas Linkermann and Br{\"u}ning, {Jens C} and Kurschat, {Christine E} and Roman-Ulrich M{\"u}ller and Wiesner, {Rudolf J} and Thomas Langer and Thomas Benzing and Brinkkoetter, {Paul Thomas}",
note = "{\textcopyright} 2015 The Authors. Published under the terms of the CC BY 4.0 license.",
year = "2015",
month = mar,
doi = "10.15252/emmm.201404916",
language = "English",
volume = "7",
pages = "275--87",
journal = "EMBO MOL MED",
issn = "1757-4676",
publisher = "Wiley-Blackwell",
number = "3",

}

RIS

TY - JOUR

T1 - Inhibition of insulin/IGF-1 receptor signaling protects from mitochondria-mediated kidney failure

AU - Ising, Christina

AU - Koehler, Sybille

AU - Brähler, Sebastian

AU - Merkwirth, Carsten

AU - Höhne, Martin

AU - Baris, Olivier R

AU - Hagmann, Henning

AU - Kann, Martin

AU - Fabretti, Francesca

AU - Dafinger, Claudia

AU - Bloch, Wilhelm

AU - Schermer, Bernhard

AU - Linkermann, Andreas

AU - Brüning, Jens C

AU - Kurschat, Christine E

AU - Müller, Roman-Ulrich

AU - Wiesner, Rudolf J

AU - Langer, Thomas

AU - Benzing, Thomas

AU - Brinkkoetter, Paul Thomas

N1 - © 2015 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2015/3

Y1 - 2015/3

N2 - Mitochondrial dysfunction and alterations in energy metabolism have been implicated in a variety of human diseases. Mitochondrial fusion is essential for maintenance of mitochondrial function and requires the prohibitin ring complex subunit prohibitin-2 (PHB2) at the mitochondrial inner membrane. Here, we provide a link between PHB2 deficiency and hyperactive insulin/IGF-1 signaling. Deletion of PHB2 in podocytes of mice, terminally differentiated cells at the kidney filtration barrier, caused progressive proteinuria, kidney failure, and death of the animals and resulted in hyperphosphorylation of S6 ribosomal protein (S6RP), a known mediator of the mTOR signaling pathway. Inhibition of the insulin/IGF-1 signaling system through genetic deletion of the insulin receptor alone or in combination with the IGF-1 receptor or treatment with rapamycin prevented hyperphosphorylation of S6RP without affecting the mitochondrial structural defect, alleviated renal disease, and delayed the onset of kidney failure in PHB2-deficient animals. Evidently, perturbation of insulin/IGF-1 receptor signaling contributes to tissue damage in mitochondrial disease, which may allow therapeutic intervention against a wide spectrum of diseases.

AB - Mitochondrial dysfunction and alterations in energy metabolism have been implicated in a variety of human diseases. Mitochondrial fusion is essential for maintenance of mitochondrial function and requires the prohibitin ring complex subunit prohibitin-2 (PHB2) at the mitochondrial inner membrane. Here, we provide a link between PHB2 deficiency and hyperactive insulin/IGF-1 signaling. Deletion of PHB2 in podocytes of mice, terminally differentiated cells at the kidney filtration barrier, caused progressive proteinuria, kidney failure, and death of the animals and resulted in hyperphosphorylation of S6 ribosomal protein (S6RP), a known mediator of the mTOR signaling pathway. Inhibition of the insulin/IGF-1 signaling system through genetic deletion of the insulin receptor alone or in combination with the IGF-1 receptor or treatment with rapamycin prevented hyperphosphorylation of S6RP without affecting the mitochondrial structural defect, alleviated renal disease, and delayed the onset of kidney failure in PHB2-deficient animals. Evidently, perturbation of insulin/IGF-1 receptor signaling contributes to tissue damage in mitochondrial disease, which may allow therapeutic intervention against a wide spectrum of diseases.

KW - Animals

KW - Gene Deletion

KW - Insulin/metabolism

KW - Mice, Inbred C57BL

KW - Mitochondria/metabolism

KW - Phosphorylation

KW - Prohibitins

KW - Protein Processing, Post-Translational

KW - Receptor, IGF Type 1/metabolism

KW - Receptor, Insulin/genetics

KW - Renal Insufficiency

KW - Repressor Proteins/genetics

KW - Ribosomal Protein S6/metabolism

KW - Signal Transduction

U2 - 10.15252/emmm.201404916

DO - 10.15252/emmm.201404916

M3 - SCORING: Journal article

C2 - 25643582

VL - 7

SP - 275

EP - 287

JO - EMBO MOL MED

JF - EMBO MOL MED

SN - 1757-4676

IS - 3

ER -