Arsenic stimulates release of cytochrome c from isolated mitochondria via induction of mitochondrial permeability transition.
Arsenic trioxide, As(III), is a known environmental toxicant, co-carcinogen, and potent chemotherapeutic agent. In model experiments with isolated rat liver mitochondria, As(III) stimulated a dose-dependent, cyclosporin A-sensitive release of cytochrome c via induction of mitochondrial permeability transition and subsequent swelling of mitochondria. Mitochondrial GSH does not seem to be a target for As(III) which, however, appears to cause oxidative modification of thiol groups of pore forming proteins, notably adenine nucleotide translocase. In mouse embryonic fibroblasts, 10 microM As(III) stimulated cytochrome c release and apoptosis via a Bax/Bak-dependent mechanism. At high concentrations (125 microM and higher), cells died by Bax/Bak-independent necrosis; at this concentration range As(III) targets mitochondria directly, particularly complex I of the mitochondrial respiratory chain. Since pyruvate, a substrate of complex I, is a predominant mitochondrial substrate in the cell, inhibition of complex I will cause mitochondrial instability and a decrease of Delta psi that facilitates permeability transition and necrotic cell death.
Department of Physical Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires, Junin 956, 1113 Buenos Aires, Argentina.
Juanita
J
Bustamante
Leta
L
Nutt
Sten
S
Orrenius
Vladimir
V
Gogvadze
D000818:Animals; D001151:Arsenic / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D045304:Cytochromes c / Q000378:metabolism*; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000502:physiology
C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D001151:Arsenic