Faculty Collaboration Database

Complex I and ATP synthase mediate membrane depolarization and matrix acidification by isoflurane in mitochondria. Eur J Pharmacol 2012 Sep 05;690(1-3):149-57

Date

07/17/2012

Pubmed ID

22796646

Pubmed Central ID

PMC3653412

DOI

10.1016/j.ejphar.2012.07.003

Scopus ID

2-s2.0-84864423478 (requires institutional sign-in at Scopus site)   28 Citations

Abstract

Short application of the volatile anesthetic isoflurane at reperfusion after ischemia exerts strong protection of the heart against injury. Mild depolarization and acidification of the mitochondrial matrix are involved in the protective mechanisms of isoflurane, but the molecular basis for these changes is not clear. In this study, mitochondrial respiration, membrane potential, matrix pH, matrix swelling, ATP synthesis and -hydrolysis, and H(2)O(2) release were assessed in isolated mitochondria. We hypothesized that isoflurane induces mitochondrial depolarization and matrix acidification through direct action on both complex I and ATP synthase. With complex I-linked substrates, isoflurane (0.5mM) inhibited mitochondrial respiration by 28 ± 10%, and slightly, but significantly depolarized membrane potential and decreased matrix pH. With complex II- and complex IV-linked substrates, respiration was not changed, but isoflurane still decreased matrix pH and depolarized mitochondrial membrane potential. Depolarization and matrix acidification were attenuated by inhibition of ATP synthase with oligomycin, but not by inhibition of mitochondrial ATP- and Ca(2+)-sensitive K(+) channels or uncoupling proteins. Isoflurane did not induce matrix swelling and did not affect ATP synthesis and hydrolysis, but decreased H(2)O(2) release in the presence of succinate in an oligomycin- and matrix pH-sensitive manner. Isoflurane modulated H(+) flux through ATP synthase in an oligomycin-sensitive manner. Our results indicate that isoflurane-induced mitochondrial depolarization and acidification occur due to inhibition of the electron transport chain at the site of complex I and increased proton flux through ATP synthase. K(+) channels and uncoupling proteins appear not to be involved in the direct effects of isoflurane on mitochondria.

Author List

Pravdic D, Hirata N, Barber L, Sedlic F, Bosnjak ZJ, Bienengraeber M

MESH terms used to index this publication - Major topics in bold

Adenosine Triphosphate
Animals
Electron Transport
Electron Transport Complex I
Hydrogen Peroxide
Hydrogen-Ion Concentration
Hydrolysis
Isoflurane
Male
Membrane Potential, Mitochondrial
Mitochondria
Mitochondrial Proton-Translocating ATPases
Potassium Channels
Rats
Rats, Wistar