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EMBO Mol Med. 2015 Mar;7(3):275-87. doi: 10.15252/emmm.201404916.

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

Author information

1
Department II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
2
Institute for Genetics, University of Cologne, Cologne, Germany Howard Hughes Medical Institute, University of California Berkeley, Berkeley, CA, USA.
3
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.
4
Center for Physiology and Pathophysiology, Institute for Vegetative Physiology, University of Cologne, Cologne, Germany.
5
Department of Molecular and Cellular Sport Medicine, Institute of Cardiovascular Research and Sport Medicine, German Sport University Cologne, Cologne, Germany.
6
Division of Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Germany.
7
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.
8
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.
9
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.
10
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.

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:

insulin; mTOR; mitochondria; podocyte

PMID:
25643582
PMCID:
PMC4364945
DOI:
10.15252/emmm.201404916
[Indexed for MEDLINE]
Free PMC Article

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