Hansson 2007 Thesis

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Hansson MJ (2007) Mitochondrial permeability transition following calcium overload. - Its role in neuronal cell death and potential as a pharmacological target. Doctoral Thesis 78p.

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Hansson MJ (2007) Doctoral Thesis

Abstract: There is currently no clinically available drug with neuroprotective properties to limit the evolving cell death following e.g. stroke or traumatic brain injury.

The mitochondrial permeability transition (mPT) is a potential pathological mechanism causing cell death in the CNS. As the name implies, the mPT is defined by a sudden increase in permeability of the inner mitochondrial membrane, whose normal impermeable state is fundamental for the bioenergetic function of mitochondria. The objective of the present studies was to characterize the mPT phenomenon in isolated rodent brain mitochondria. Mitochondria serve an important role in cellular calcium homeostasis and buffer transient increases in calcium, but mitochondrial calcium overload is also the prime trigger for mPT. In the present studies, we found that brain mitochondria readily undergo changes attributable to mPT induction such as swelling, loss of membrane potential, uncoupling of oxidative phosphorylation and respiratory inhibition. The mitochondrial generation of reactive oxygen species (ROS) was also increased following mPT, and mitochondria became permeable to NAD(H).

Cyclosporin A (CsA) binds to the mitochondrial protein cyclophilin D (CypD) and can thereby inhibit mPT, an effect that is unrelated to its immunosuppressive action, and mPT in brain mitochondria was found to be highly sensitive to CsA inhibition. CsA has demonstrated prominent neuroprotective properties in several different animal models of neurological disease, and recent experiments subjecting mice lacking CypD to ischemia support the conclusion that the effect of CsA at least in this model is mediated by mPT inhibition. A library of CsA analogs was evaluated for mPT-inhibiting and ROS-reducing properties, and two newly developed nonimmunosuppressive CsA analogs were found to be potent inhibitors of mPT already at nanomolar concentrations.

Mitochondria take up free calcium ions but retain them as inactive calcium phosphate complexes in order to prevent mPT. We find that increasing the conductance of potassium increases the pH of the matrix and this enhances the mitochondrial buffering of calcium, probably by increasing the complexation of calcium.

Drugs that inhibit mPT or indirectly prevent mPT by enhancing the mitochondrial complexation of calcium and thereby their resistance to calcium overload may therefore prove to be successful strategies in limiting accidental cell death in the CNS.


O2k-Network Lab: SE Lund Elmer E


Labels: MiParea: Respiration, Pharmacology;toxicology 

Stress:Permeability transition, Oxidative stress;RONS  Organism: Mouse  Tissue;cell: Nervous system  Preparation: Isolated mitochondria 

Regulation: Calcium  Coupling state: OXPHOS  Pathway:HRR: Oxygraph-2k 

Pharmacology, Biotechnology