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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Deletion
  • Insulin / metabolism*
  • Mice, Inbred C57BL
  • Mitochondria / metabolism*
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Receptor, IGF Type 1 / metabolism*
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism*
  • Renal Insufficiency*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Ribosomal Protein S6 / metabolism
  • Signal Transduction*

Substances

  • Insulin
  • Repressor Proteins
  • Ribosomal Protein S6
  • prohibitin
  • Receptor, IGF Type 1
  • Receptor, Insulin