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

Ising, C., Koehler, S., Brahler, S., Merkwirth, C., Hohne, M., Baris, O. R., et al. (2015). Inhibition of insulin/IGF-1 receptor signaling protects from mitochondria-mediated kidney failure. EMBO Mol Med, 7(3), 275-87. doi:10.15252/emmm.201404916.

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https://www.ncbi.nlm.nih.gov/pubmed/25643582 (beliebiger Volltext)
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 Urheber:
Ising, C., Autor
Koehler, S., Autor
Brahler, S., Autor
Merkwirth, C., Autor
Hohne, M., Autor
Baris, O. R., Autor
Hagmann, H., Autor
Kann, M., Autor
Fabretti, F., Autor
Dafinger, C., Autor
Bloch, W., Autor
Schermer, B., Autor
Linkermann, A., Autor
Bruning, J. C., Autor
Kurschat, C. E., Autor
Muller, R. U., Autor
Wiesner, R. J., Autor
Langer, T.1, Autor           
Benzing, T., Autor
Brinkkoetter, P. T., Autor
Affiliations:
1Department Langer - Mitochondrial Proteostasis, Max Planck Institute for Biology of Ageing, Max Planck Society, ou_3393994              

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Schlagwörter: Animals Gene Deletion Insulin/*metabolism Mice, Inbred C57BL Mitochondria/*metabolism Phosphorylation Protein Processing, Post-Translational Receptor, IGF Type 1/*metabolism Receptor, Insulin/genetics/*metabolism *Renal Insufficiency Repressor Proteins/genetics/metabolism Ribosomal Protein S6/metabolism *Signal Transduction insulin mTOR mitochondria podocyte
 Zusammenfassung: 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.

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 Datum: 2015-032015-02-04
 Publikationsstatus: Erschienen
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 Identifikatoren: Anderer: 25643582
DOI: 10.15252/emmm.201404916
ISSN: 1757-4684 (Electronic)1757-4676 (Linking)
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Titel: EMBO Mol Med
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: -
Seiten: - Band / Heft: 7 (3) Artikelnummer: - Start- / Endseite: 275 - 87 Identifikator: -