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 mem...
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| Format: | Article |
| Language: | English |
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Springer Nature
2015-02-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201404916 |
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| author | Christina Ising Sybille Koehler Sebastian Brähler Carsten Merkwirth Martin Höhne Olivier R Baris Henning Hagmann Martin Kann Francesca Fabretti Claudia Dafinger Wilhelm Bloch Bernhard Schermer Andreas Linkermann Jens C Brüning Christine E Kurschat Roman‐Ulrich Müller Rudolf J Wiesner Thomas Langer Thomas Benzing Paul Thomas Brinkkoetter |
| author_facet | Christina Ising Sybille Koehler Sebastian Brähler Carsten Merkwirth Martin Höhne Olivier R Baris Henning Hagmann Martin Kann Francesca Fabretti Claudia Dafinger Wilhelm Bloch Bernhard Schermer Andreas Linkermann Jens C Brüning Christine E Kurschat Roman‐Ulrich Müller Rudolf J Wiesner Thomas Langer Thomas Benzing Paul Thomas Brinkkoetter |
| author_sort | Christina Ising |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-aaed36cafd0a43ab8e7e6120f044f0e0 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2015-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-aaed36cafd0a43ab8e7e6120f044f0e02025-08-20T04:03:00ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842015-02-017327528710.15252/emmm.201404916Inhibition of insulin/IGF‐1 receptor signaling protects from mitochondria‐mediated kidney failureChristina Ising0Sybille Koehler1Sebastian Brähler2Carsten Merkwirth3Martin Höhne4Olivier R Baris5Henning Hagmann6Martin Kann7Francesca Fabretti8Claudia Dafinger9Wilhelm Bloch10Bernhard Schermer11Andreas Linkermann12Jens C Brüning13Christine E Kurschat14Roman‐Ulrich Müller15Rudolf J Wiesner16Thomas Langer17Thomas Benzing18Paul Thomas Brinkkoetter19Department II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of CologneDepartment II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of CologneDepartment II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of CologneInstitute for Genetics, University of CologneDepartment II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of CologneCenter for Physiology and Pathophysiology, Institute for Vegetative Physiology, University of CologneDepartment II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of CologneDepartment II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of CologneDepartment II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of CologneDepartment II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of CologneDepartment of Molecular and Cellular Sport Medicine, Institute of Cardiovascular Research and Sport Medicine, German Sport University CologneDepartment II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of CologneDivision of Nephrology and Hypertension, Christian‐Albrechts‐UniversityCologne Cluster of Excellence on Cellular Stress Responses in Ageing‐Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol), University of CologneDepartment II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of CologneDepartment II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of CologneCenter for Physiology and Pathophysiology, Institute for Vegetative Physiology, University of CologneInstitute for Genetics, University of CologneDepartment II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of CologneDepartment II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of CologneAbstract 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.https://doi.org/10.15252/emmm.201404916insulinmitochondriamTORpodocyte |
| spellingShingle | Christina Ising Sybille Koehler Sebastian Brähler Carsten Merkwirth Martin Höhne Olivier R Baris Henning Hagmann Martin Kann Francesca Fabretti Claudia Dafinger Wilhelm Bloch Bernhard Schermer Andreas Linkermann Jens C Brüning Christine E Kurschat Roman‐Ulrich Müller Rudolf J Wiesner Thomas Langer Thomas Benzing Paul Thomas Brinkkoetter Inhibition of insulin/IGF‐1 receptor signaling protects from mitochondria‐mediated kidney failure EMBO Molecular Medicine insulin mitochondria mTOR podocyte |
| title | Inhibition of insulin/IGF‐1 receptor signaling protects from mitochondria‐mediated kidney failure |
| title_full | Inhibition of insulin/IGF‐1 receptor signaling protects from mitochondria‐mediated kidney failure |
| title_fullStr | Inhibition of insulin/IGF‐1 receptor signaling protects from mitochondria‐mediated kidney failure |
| title_full_unstemmed | Inhibition of insulin/IGF‐1 receptor signaling protects from mitochondria‐mediated kidney failure |
| title_short | Inhibition of insulin/IGF‐1 receptor signaling protects from mitochondria‐mediated kidney failure |
| title_sort | inhibition of insulin igf 1 receptor signaling protects from mitochondria mediated kidney failure |
| topic | insulin mitochondria mTOR podocyte |
| url | https://doi.org/10.15252/emmm.201404916 |
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