title: Minocycline chelates Ca2+, binds to membranes, and depolarizes mitochondria by formation of Ca2+-dependent ion channels.
abstract: Minocycline (an anti-inflammatory drug approved by the FDA) has been reported to be effective in mouse models of amyotrophic lateral sclerosis and Huntington disease. It has been suggested that the beneficial effects of minocycline are related to its ability to influence mitochondrial functioning. We tested the hypothesis that minocycline directly inhibits the Ca(2+)-induced permeability transition in rat liver mitochondria. Our data show that minocycline does not directly inhibit the mitochondrial permeability transition. However, minocycline has multiple effects on mitochondrial functioning. First, this drug chelates Ca(2+) ions. Secondly, minocycline, in a Ca(2+)-dependent manner, binds to mitochondrial membranes. Thirdly, minocycline decreases the proton-motive force by forming ion channels in the inner mitochondrial membrane. Channel formation was confirmed with two bilayer lipid membrane models. We show that minocycline, in the presence of Ca(2+), induces selective permeability for small ions. We suggest that the beneficial action of minocycline is related to the Ca(2+)-dependent partial uncoupling of mitochondria, which indirectly prevents induction of the mitochondrial permeability transition.
authors.affiliation: A.N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, 119992, Russia.
authors.forename: Yuri N
authors.initials: YN
authors.lastname: Antonenko
authors.forename: Tatyana I
authors.initials: TI
authors.lastname: Rokitskaya
authors.forename: Arthur J L
authors.initials: AJ
authors.lastname: Cooper
authors.forename: Boris F
authors.initials: BF
authors.lastname: Krasnikov
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008911:Minocycline / Q000737:chemistry / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism*; D015394:Molecular Structure; D051381:Rats
chemical_list: D015220:Calcium Channels; D002614:Chelating Agents; D008911:Minocycline; D002118:Calcium