title: Brain-derived respiring mitochondria exhibit homogeneous, complete and cyclosporin-sensitive permeability transition.
abstract: The mitochondrial permeability transition (mPT) is increasingly implicated in neuronal cell death. In the present study, isolated respiring brain mitochondria were examined for their ability to undergo calcium-induced mPT and their sensitivity to mPT inhibition by cyclosporin A (CsA). Previous studies have suggested a heterogeneous response to calcium, a limitation of CsA inhibition, and a relative resistance in the ability of respiring brain mitochondria to undergo mPT. Using fluorometric and electron microscopic analyses, we found that virtually the whole population of respiring brain mitochondria readily undergo mPT and swell upon calcium exposure. Further, brain mitochondria were highly sensitive to CsA which potentiated morphological recovery after transient swelling as well as completely blocked mPT induction in the presence of a low concentration of ADP. Using flow cytometry, which allows analysis of individual mitochondria, we demonstrate that both brain and liver mitochondria display homogeneous responses to calcium-induced mPT. We conclude that the mPT is one likely target for the broad in vivo neuroprotective effects displayed by CsA when allowed to penetrate the blood-brain barrier, and that development of compounds inhibiting mPT may prove beneficial for the treatment of severe brain disease.
authors.affiliation: Laboratory for Experimental Brain Research, Wallenberg Neuroscience Center, Lund University, Sweden. magnus.hansson@expbr.lu.se
authors.forename: Magnus J
authors.initials: MJ
authors.lastname: Hansson
authors.forename: Roland
authors.initials: R
authors.lastname: Månsson
authors.forename: Gustav
authors.initials: G
authors.lastname: Mattiasson
authors.forename: Jonas
authors.initials: J
authors.lastname: Ohlsson
authors.forename: Jenny
authors.initials: J
authors.lastname: Karlsson
authors.forename: Marcus F
authors.initials: MF
authors.lastname: Keep
authors.forename: Eskil
authors.initials: E
authors.lastname: Elmér
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D002118:Calcium / Q000494:pharmacology; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004791:Enzyme Inhibitors; D000244:Adenosine Diphosphate; D016572:Cyclosporine; D002118:Calcium