Impairment of mitochondrial function by minocycline.
There is an ongoing debate on the presence of beneficial effects of minocycline (MC), a tetracycline-like antibiotic, on the preservation of mitochondrial functions under conditions promoting mitochondria-mediated apoptosis. Here, we present a multiparameter study on the effects of MC on isolated rat liver mitochondria (RLM) suspended either in a KCl-based or in a sucrose-based medium. We found that the incubation medium used strongly affects the response of RLM to MC. In KCl-based medium, but not in sucrose-based medium, MC triggered mitochondrial swelling and cytochrome c release. MC-dependent swelling was associated with mitochondrial depolarization and a decrease in state 3 as well as uncoupled respiration. Swelling of RLM in KCl-based medium indicates that MC permeabilizes the inner mitochondrial membrane (IMM) to K(+) and Cl(-). This view is supported by our findings that MC-induced swelling in the KCl-based medium was partly suppressed by N,N'-dicyclohexylcarbodiimide (an inhibitor of IMM-linked K(+)-transport) and tributyltin (an inhibitor of the inner membrane anion channel) and that swelling was less pronounced when RLM were suspended in choline chloride-based medium. In addition, we observed a rapid MC-induced depletion of endogenous Mg(2+) from RLM, an event that is known to activate ion-conducting pathways within the IMM. Moreover, MC abolished the Ca(2+) retention capacity of RLM irrespective of the incubation medium used, most likely by triggering permeability transition. In summary, we found that MC at low micromolar concentrations impairs several energy-dependent functions of mitochondria in vitro.
Kupsch
Kathleen
K
Institute of Biochemistry and Cell Biology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany. kkupsch@web.de
Hertel
Silvia
S
Kreutzmann
Peter
P
Wolf
Gerald
G
Wallesch
Claus-Werner
CW
Siemen
Detlef
D
Schönfeld
Peter
P
D000818:Animals; D004024:Dicyclohexylcarbodiimide / Q000494:pharmacology; D008274:Magnesium / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008911:Minocycline / Q000494:pharmacology*; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D014220:Trialkyltin Compounds / Q000494:pharmacology
D014220:Trialkyltin Compounds; D009243:NAD; C011559:tributyltin; D004024:Dicyclohexylcarbodiimide; D008911:Minocycline; D008274:Magnesium