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.
authors: Department II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors: Christina
authors: C
authors: Ising
authors: Department II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors: Sybille
authors: S
authors: Koehler
authors: Department II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors: Sebastian
authors: S
authors: Brähler
authors: Institute for Genetics, University of Cologne, Cologne, Germany Howard Hughes Medical Institute, University of California Berkeley, Berkeley, CA, USA.
authors: Carsten
authors: C
authors: Merkwirth
authors: Department II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol) University of Cologne, Cologne, Germany.
authors: Martin
authors: M
authors: Höhne
authors: Center for Physiology and Pathophysiology, Institute for Vegetative Physiology, University of Cologne, Cologne, Germany.
authors: Olivier R
authors: OR
authors: Baris
authors: Department II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors: Henning
authors: H
authors: Hagmann
authors: Department II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors: Martin
authors: M
authors: Kann
authors: Department II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors: Francesca
authors: F
authors: Fabretti
authors: Department II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors: Claudia
authors: C
authors: Dafinger
authors: Department of Molecular and Cellular Sport Medicine, Institute of Cardiovascular Research and Sport Medicine, German Sport University Cologne, Cologne, Germany.
authors: Wilhelm
authors: W
authors: Bloch
authors: Department II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol) University of Cologne, Cologne, Germany.
authors: Bernhard
authors: B
authors: Schermer
authors: Division of Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Germany.
authors: Andreas
authors: A
authors: Linkermann
authors: Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol) University of Cologne, Cologne, Germany Max Planck Institute for Metabolism Research, Cologne, Germany Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Cologne, Germany.
authors: Jens C
authors: JC
authors: Brüning
authors: Department II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol) University of Cologne, Cologne, Germany.
authors: Christine E
authors: CE
authors: Kurschat
authors: Department II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol) University of Cologne, Cologne, Germany.
authors: Roman-Ulrich
authors: RU
authors: Müller
authors: Center for Physiology and Pathophysiology, Institute for Vegetative Physiology, University of Cologne, Cologne, Germany.
authors: Rudolf J
authors: RJ
authors: Wiesner
authors: Institute for Genetics, University of Cologne, Cologne, Germany Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol) University of Cologne, Cologne, Germany.
authors: Thomas
authors: T
authors: Langer
authors: Department II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol) University of Cologne, Cologne, Germany thomas.benzing@uk-koeln.de paul.brinkkoetter@uk-koeln.de.
authors: Thomas
authors: T
authors: Benzing
authors: Department II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany thomas.benzing@uk-koeln.de paul.brinkkoetter@uk-koeln.de.
authors: Paul Thomas
authors: PT
authors: Brinkkoetter
mesh_terms: D000818:Animals; D017353:Gene Deletion; D007328:Insulin / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D010766:Phosphorylation; D000091402:Prohibitins; D011499:Protein Processing, Post-Translational; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D051437:Renal Insufficiency; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007328:Insulin; C000717331:PHB2 protein, human; C000717333:Phb2 protein, mouse; D000091402:Prohibitins; D012097:Repressor Proteins; D038601:Ribosomal Protein S6; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin
keywords: insulin; mTOR; mitochondria; podocyte
references: EMBO J. 2000 Jun 1;19(11):2444-51
references: 10835343
references: Trends Mol Med. 2014 May;20(5):282-92
references: 24508276
references: Genesis. 2003 Jan;35(1):39-42
references: 12481297
references: J Biol Chem. 2003 Aug 22;278(34):32091-9
references: 12794069
references: Crit Care. 2004 Oct;8(5):389-94
references: 15469602
references: Nephrol Dial Transplant. 1998 Jun;13(6):1368-73
references: 9641162
references: Mol Cell Biol. 1999 May;19(5):3435-42
references: 10207067
references: Mol Biol Cell. 2005 Jan;16(1):248-59
references: 15525670
references: Mol Cell Biol. 2005 Mar;25(5):1989-99
references: 15713652
references: Diabetes. 2005 Nov;54(11):3095-102
references: 16249431
references: Kidney Int. 2007 Jul;72(1):26-36
references: 17457377
references: Genes Dev. 2008 Feb 15;22(4):476-88
references: 18281461
references: Exp Cell Res. 2008 Mar 10;314(5):988-96
references: 18258228
references: Ann Neurol. 2008 Apr;63(4):444-53
references: 18389497
references: Biochim Biophys Acta. 2009 Jan;1793(1):27-32
references: 18558096
references: J Cell Biol. 2009 Feb 23;184(4):583-96
references: 19221197
references: Nature. 2009 Oct 8;461(7265):793-7
references: 19812672
references: J Cell Sci. 2009 Nov 1;122(Pt 21):3823-30
references: 19889967
references: Genesis. 2010 Jul;48(7):446-51
references: 20641128
references: Cell Metab. 2010 Oct 6;12(4):329-40
references: 20889126
references: Microsc Res Tech. 2010 Oct;73(11):1019-29
references: 20232465
references: J Clin Invest. 2011 Jun;121(6):2197-209
references: 21606591
references: J Clin Invest. 2011 Jun;121(6):2181-96
references: 21606597
references: PLoS One. 2011;6(8):e23525
references: 21858155
references: Stem Cells. 2011 Sep;29(9):1459-68
references: 21780252
references: Biochem J. 2012 Jan 1;441(1):1-21
references: 22168436
references: Cell. 2012 Mar 16;148(6):1145-59
references: 22424226
references: Curr Opin Nephrol Hypertens. 2012 May;21(3):251-7
references: 22388550
references: Nat Methods. 2012 Jul;9(7):676-82
references: 22743772
references: Exp Dermatol. 2012 Aug;21(8):640-2
references: 22776003
references: PLoS Genet. 2012;8(11):e1003021
references: 23144624
references: Mol Biol Cell. 2013 Mar;24(5):659-67
references: 23283981
references: J Clin Invest. 2013 Mar;123(3):951-7
references: 23454757
references: Nat Rev Nephrol. 2013 Jun;9(6):328-36
references: 23609563
references: PLoS Genet. 2013 Jun;9(6):e1003563
references: 23785301
references: Am J Physiol Renal Physiol. 2013 Aug 15;305(4):F520-31
references: 23761667
references: Int J Biochem Cell Biol. 2013 Sep;45(9):2109-18
references: 23806869
references: Aging Cell. 2013 Dec;12(6):1050-61
references: 23837470
references: PLoS One. 2013;8(12):e83408
references: 24349506
references: Science. 2013 Dec 20;342(6165):1524-8
references: 24231806
references: Protein Sci. 2002 Oct;11(10):2471-8
references: 12237468