title: Functional and pharmacological characteristics of permeability transition in isolated human heart mitochondria.
abstract: The objective of the present study was to validate the presence and explore the characteristics of mitochondrial permeability transition (mPT) in isolated mitochondria from human heart tissue in order to investigate if previous findings in animal models of cardiac disorders are translatable to human disease. Mitochondria were rapidly isolated from fresh atrial tissue samples obtained from 14 patients undergoing Maze surgery due to atrial fibrillation. Human heart mitochondria exhibited typical mPT characteristics upon calcium overload such as swelling, evaluated by changes in light scattering, inhibition of respiration and loss of respiratory coupling. Swelling was a morphologically reversible event following transient calcium challenge. Calcium retention capacity (CRC), a quantitative measure of mPT sensitivity assayed by following extramitochondrial [Ca(2+)] and changes in respiration during a continuous calcium infusion, was significantly increased by cyclophilin D (CypD) inhibitors. The thiol-reactive oxidant phenylarsine oxide sensitized mitochondria to calcium-induced mPT. Release of the pro-apoptotic intermembrane protein cytochrome c was increased after, but not before, calcium discharge and respiratory inhibition in the CRC assay. From the present study, we conclude that adult viable heart mitochondria have a CypD- and oxidant-regulated mPT. The findings support that inhibition of mPT may be a relevant pharmacological target in human cardiac disease and may underlie the beneficial effect of cyclosporin A in reperfusion injury.
authors.affiliation: Mitochondrial Pathophysiology Unit, Skåne University Hospital & Lund University, Lund, Sweden.
authors.forename: Saori
authors.initials: S
authors.lastname: Morota
authors.forename: Theodor
authors.initials: T
authors.lastname: Manolopoulos
authors.forename: Atli
authors.initials: A
authors.lastname: Eyjolfsson
authors.forename: Per-Ola
authors.initials: PO
authors.lastname: Kimblad
authors.forename: Per
authors.initials: P
authors.lastname: Wierup
authors.forename: Carsten
authors.initials: C
authors.lastname: Metzsch
authors.forename: Sten
authors.initials: S
authors.lastname: Blomquist
authors.forename: Magnus J
authors.initials: MJ
authors.lastname: Hansson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002118:Calcium / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D008933:Mitochondrial Swelling / Q000187:drug effects / Q000502:physiology; D016877:Oxidants / Q000378:metabolism; D010539:Permeability / Q000187:drug effects*
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D016877:Oxidants; D016572:Cyclosporine; D045304:Cytochromes c; D021983:Cyclophilins; D002118:Calcium