Ising, Christina ORCID: 0000-0002-7267-3488, Koehler, Sybille, Braehler, Sebastian, Merkwirth, Carsten ORCID: 0000-0001-8895-3495, Hoehne, Martin, Baris, Olivier R., Hagmann, Henning, Kann, Martin, Fabretti, Francesca, Dafinger, Claudia, Bloch, Wilhelm, Schermer, Bernhard ORCID: 0000-0002-5194-9000, Linkermann, Andreas ORCID: 0000-0001-6287-9725, Bruening, Jens C., Kurschat, Christine E., Mueller, Roman-Ulrich, Wiesner, Rudolf J., Langer, Thomas ORCID: 0000-0003-1250-1462, Benzing, Thomas and Brinkkoetter, Paul Thomas (2015). Inhibition of insulin/IGF-1 receptor signaling protects from mitochondria-mediated kidney failure. EMBO Mol. Med., 7 (3). S. 275 - 288. HOBOKEN: WILEY. ISSN 1757-4684

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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 mayallow therapeutic intervention against a wide spectrum of diseases.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Ising, ChristinaUNSPECIFIEDorcid.org/0000-0002-7267-3488UNSPECIFIED
Koehler, SybilleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braehler, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merkwirth, CarstenUNSPECIFIEDorcid.org/0000-0001-8895-3495UNSPECIFIED
Hoehne, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baris, Olivier R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hagmann, HenningUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kann, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fabretti, FrancescaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dafinger, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bloch, WilhelmUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schermer, BernhardUNSPECIFIEDorcid.org/0000-0002-5194-9000UNSPECIFIED
Linkermann, AndreasUNSPECIFIEDorcid.org/0000-0001-6287-9725UNSPECIFIED
Bruening, Jens C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kurschat, Christine E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, Roman-UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wiesner, Rudolf J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Langer, ThomasUNSPECIFIEDorcid.org/0000-0003-1250-1462UNSPECIFIED
Benzing, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brinkkoetter, Paul ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-406763
DOI: 10.15252/emmm.201404916
Journal or Publication Title: EMBO Mol. Med.
Volume: 7
Number: 3
Page Range: S. 275 - 288
Date: 2015
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1757-4684
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CRISTAE MORPHOGENESIS; DIABETIC-NEPHROPATHY; GLOMERULAR PODOCYTE; CELL-PROLIFERATION; MOUSE MODEL; IN-VIVO; PROHIBITINS; TARGET; MTOR; MICEMultiple languages
Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/40676

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