HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Induction of the permeability transition pore in cells depleted of mitochondrial DNA.

Abstract
Respiratory complexes are believed to play a role in the function of the mitochondrial permeability transition pore (PTP), whose dysregulation affects the process of cell death and is involved in a variety of diseases, including cancer and degenerative disorders. We investigated here the PTP in cells devoid of mitochondrial DNA (ρ(0) cells), which lack respiration and constitute a model for the analysis of mitochondrial involvement in several pathological conditions. We observed that mitochondria of ρ(0) cells maintain a membrane potential and that this is readily dissipated after displacement of hexokinase (HK) II from the mitochondrial surface by treatment with either the drug clotrimazole or with a cell-permeant HK II peptide, or by placing ρ(0) cells in a medium without serum and glucose. The PTP inhibitor cyclosporin A (CsA) could decrease the mitochondrial depolarization induced by either HK II displacement or by nutrient depletion. We also found that a fraction of the kinases ERK1/2 and GSK3α/β is located in the mitochondrial matrix of ρ(0) cells, and that glucose and serum deprivation caused concomitant ERK1/2 inhibition and GSK3α/β activation with the ensuing phosphorylation of cyclophilin D, the mitochondrial target of CsA. GSK3α/β inhibition with indirubin-3'-oxime decreased PTP-induced cell death in ρ(0) cells following nutrient ablation. These findings indicate that ρ(0) cells are equipped with a functioning PTP, whose regulatory mechanisms are similar to those observed in cancer cells, and suggest that escape from PTP opening is a survival factor in this model of mitochondrial diseases. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012).
AuthorsIonica Masgras, Andrea Rasola, Paolo Bernardi
JournalBiochimica et biophysica acta (Biochim Biophys Acta) Vol. 1817 Issue 10 Pg. 1860-6 (Oct 2012) ISSN: 0006-3002 [Print] Netherlands
PMID22402226 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier B.V. All rights reserved.
Chemical References
  • DNA, Mitochondrial
  • Enzyme Inhibitors
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Cyclosporine
  • Hexokinase
  • Glycogen Synthase Kinase 3 beta
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Glycogen Synthase Kinase 3
Topics
  • Cell Line, Tumor
  • Cyclosporine (pharmacology)
  • DNA, Mitochondrial (genetics, metabolism)
  • Enzyme Activation (drug effects)
  • Enzyme Inhibitors (pharmacology)
  • Glycogen Synthase Kinase 3 (genetics, metabolism)
  • Glycogen Synthase Kinase 3 beta
  • Hexokinase (genetics, metabolism)
  • Humans
  • Membrane Potential, Mitochondrial (genetics)
  • Mitochondrial Diseases (genetics, metabolism)
  • Mitochondrial Membrane Transport Proteins (antagonists & inhibitors, genetics, metabolism)
  • Mitochondrial Permeability Transition Pore
  • Mitogen-Activated Protein Kinase 1 (genetics, metabolism)
  • Mitogen-Activated Protein Kinase 3 (genetics, metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: