title: Minocycline exerts uncoupling and inhibiting effects on mitochondrial respiration through adenine nucleotide translocase inhibition.
abstract: The present study was aimed to provide a better understanding of the mitochondria-targeted actions of minocycline (MC), a second-generation tetracycline which has cytoprotective effects. Although the specific mechanisms underlying its activity remained elusive, considerable amounts of data indicated mitochondria as the primary pharmacological target of MC. Previous reports have shown that MC affects the oxygen-uptake rate by isolated mitochondria in different respiratory states. Here, we report on the effect of MC, in the range 50-200μM, on mitochondrial respiration. State 3 respiration titration with carboxyatractyloside revealed that MC inhibits the adenine nucleotide translocase. Furthermore, we analyze MC channel-forming capacity in the lipid membrane bilayer. Our results confirmed the crucial role of Δψ and showed a dependence on Ca(2+) for MC to have an effect on mitochondria. Our data also indicated that outer and inner mitochondrial membranes contribute differently to this effect, involving the presence of Δψ (the inner membrane) and VDAC (the outer membrane). Data from three isosmotic media indicate that MC does not increase the permeability of the inner membrane to protons or potassium. In addition, by using mitoplasts and ruthenium red, we showed that Ca(2+) uptake is not involved in the MC effect, suggesting involvement of VDAC in the MC interaction with the outer membrane. Our data contribute to unravel the mechanisms behind the mitochondria-targeted activity of the cytoprotective drug MC.
authors: Grupo de Neurofarmacología, IDINE-UCLM, Albacete, Spain.
authors: Maria D
authors: MD
authors: Cuenca-Lopez
authors: Andonis
authors: A
authors: Karachitos
authors: Luca
authors: L
authors: Massarotto
authors: Paulo J
authors: PJ
authors: Oliveira
authors: Norberto
authors: N
authors: Aguirre
authors: María F
authors: MF
authors: Galindo
authors: Hanna
authors: H
authors: Kmita
authors: Joaquin
authors: J
authors: Jordán
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects*; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008911:Minocycline / Q000494:pharmacology*; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D000226:Mitochondrial ADP, ATP Translocases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014475:Uncoupling Agents / Q000494:pharmacology*; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D014475:Uncoupling Agents; D050994:Voltage-Dependent Anion Channels; D000226:Mitochondrial ADP, ATP Translocases; D025261:Mitochondrial Proton-Translocating ATPases; D008911:Minocycline; D002118:Calcium