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.
Bustamante
Juanita
J
Department of Physical Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires, Junin 956, 1113 Buenos Aires, Argentina.
Nutt
Leta
L
Orrenius
Sten
S
Gogvadze
Vladimir
V
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