Interaction of the antibiotic minocycline with liver mitochondria - role of membrane permeabilization in the impairment of respiration

FEBS J. 2013 Dec;280(24):6589-99. doi: 10.1111/febs.12563. Epub 2013 Oct 30.

Abstract

Several studies have proposed that the antibiotic minocycline (MC) has cytoprotective activities. Nevertheless, when cells have been exposed to MC at micromolar concentrations, detrimental effects have been also observed. Despite the known inhibitory activity of MC on ATP synthesis and the Ca(2+) retention capacity of isolated rat liver and brain mitochondria, the underlying mechanism is still debated. Here, we present further arguments supporting our concept that MC acting on rat liver mitochondria suspended in KCl medium permeabilizes the inner membrane. Supplementation of the medium with cytochrome c and NAD(+) strongly enhanced the respiration of MC-treated mitochondria, thus partly preventing or reversing the inhibitory effect of MC on state 3 or uncoupled respiration. These results indicate that MC produced depletion of mitochondrial cytochrome c and NAD(+) , thus impairing mitochondrial respiration. In addition, NADH oxidation by alamethicin-permeabilized mitochondria supplemented with cytochrome c was insensitive to 200 μm MC, arguing against direct impairment of respiratory chain complexes by MC. Finally, a surprising feature of MC was its accumulation or binding by intact rat liver mitochondria, but not by mitochondria permeabilized with alamethicin or disrupted by freezing and thawing.

Keywords: minocyline; mitochondria; respiration; swelling; transmembrane potential.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alamethicin / pharmacology
  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / pharmacology
  • Cell Respiration / drug effects*
  • Cytochromes c / metabolism
  • Membrane Potential, Mitochondrial / drug effects*
  • Minocycline / pharmacology*
  • Mitochondria, Liver / drug effects
  • Mitochondria, Liver / metabolism*
  • Mitochondrial Membranes / drug effects
  • Mitochondrial Swelling / drug effects*
  • NAD / metabolism
  • Oxygen Consumption / drug effects
  • Phosphorylation / drug effects
  • Proton Ionophores / pharmacology
  • Rats
  • Rats, Wistar

Substances

  • Anti-Bacterial Agents
  • Proton Ionophores
  • NAD
  • Alamethicin
  • Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
  • Cytochromes c
  • Minocycline