Almitrine, a new kind of energy-transduction inhibitor acting on mitochondrial ATP synthase.
At low concentrations, almitrine inhibits yeast cell multiplication by acting on oxidative metabolism. Studies on isolated mitochondria display the following features: (i) almitrine inhibits ATPase activity and decreases ATP/O ratio during oxidative phosphorylation; (ii) no direct effect on respiration can be evidenced; (iii) ATP/O value decreases without any change in the magnitude of delta p; (iv) the higher the ATP synthesis and respiratory fluxes, the larger is the decrease in ATP/O ratio induced by almitrine. These results indicate that almitrine does not act as a classical protonophoric uncoupler nor as previously studied non protonophoric uncouplers (e.g., general anesthetics). Our data show a direct inhibitory effect of almitrine on ATPase-ATP synthase complex. But, in contrast to the classical inhibitors of this complex, almitrine decreases the ATP/O ratio in a flux-dependent manner. Thus, almitrine could induce either an intrinsic uncoupling of H+/-ATPase (i.e., slip in this proton pump) or a change in the mechanistic H+/ATP stoichiometry at the ATPase level.
Rigoulet
M
M
Institut de Biologie et Neurochimie, C.N.R.S., Bordeaux, France.
Ouhabi
R
R
Leverve
X
X
Putod-Paramelle
F
F
Guérin
B
B
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D015765:Almitrine; D002455:Cell Division / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology*; D007700:Kinetics; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000254:growth & development / Q000378:metabolism; D014475:Uncoupling Agents / Q000494:pharmacology
D006131:Growth Inhibitors; D010879:Piperazines; D014475:Uncoupling Agents; D000255:Adenosine Triphosphate; D015765:Almitrine; D006180:Proton-Translocating ATPases