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

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. He...

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Published in:	EMBO molecular medicine 2015-03, Vol.7 (3), p.275-287
Main Authors:	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
Format:	Article
Language:	eng
Subjects:	Animals Cell differentiation Clonal deletion Energy metabolism Funding Gene Deletion Insulin Insulin - metabolism Insulin-like growth factors Kidney diseases Kidney failure Kidneys Life Sciences Mice, Inbred C57BL Mitochondria Mitochondria - metabolism mTOR Phosphorylation Physiological aspects podocyte Prohibitin Protein Processing, Post-Translational Proteins Proteinuria Rapamycin Receptor, IGF Type 1 - metabolism Receptor, Insulin - genetics Receptor, Insulin - metabolism Renal failure Renal Insufficiency Repressor Proteins - genetics Repressor Proteins - metabolism Ribosomal Protein S6 - metabolism Signal Transduction TOR protein
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Summary:	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. Synopsis Podocyte‐specific PHB2 loss results in severe kidney disease that is alleviated by insulin and IGF‐1 receptors deletion or rapamycin treatment, demonstrating not only a causal link between mitochondrial dysfunction and kidney disease but also putative therapeutic avenues. Deletion of the mitochondrial protein PHB2 in glomerular podocytes caused progressive proteinuria and death of the animals due to end‐stage kidney failure. Contrary to generally held beliefs loss of PHB2 did not cause overt defects in mitochondrial respiratory activity or increased production of ROS but was accompanied by hyperactive insulin/IGF‐1 receptor signaling. Inhibition of the insulin/IGF‐1 signaling system through genetic deletion of insulin receptor alone or in combination with the IGF‐1 receptor or treatment with mTOR inhibitor rapamycin, alleviated renal disease and delayed the onset of kidney failure in PHB2‐deficient animals. Podocyte‐specific PHB2 loss results in severe kidney disease that is alleviated by insulin and IGF‐1 receptors deletion or rapamycin treatment, demonstrating not only a causal link between mitochondrial dysfunction and kidney disease but also putative therapeutic avenues.
ISSN:	1757-4676 1757-4684