Arsenic stimulates release of cytochrome c from isolated mitochondria via induction of mitochondrial permeability transition

Arsenic stimulates release of cytochrome c from isolated mitochondria via induction of... 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 μM As(III) stimulated cytochrome c release and apoptosis via a Bax/Bak-dependent mechanism. At high concentrations (125 μM 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 Δψ that facilitates permeability transition and necrotic cell death. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Toxicology and Applied Pharmacology Elsevier

Arsenic stimulates release of cytochrome c from isolated mitochondria via induction of mitochondrial permeability transition

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Publisher
Elsevier
Copyright
Copyright © 2005 Elsevier Inc.
ISSN
0041-008x
D.O.I.
10.1016/j.taap.2005.01.024
Publisher site
See Article on Publisher Site

Abstract

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 μM As(III) stimulated cytochrome c release and apoptosis via a Bax/Bak-dependent mechanism. At high concentrations (125 μM 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 Δψ that facilitates permeability transition and necrotic cell death.

Journal

Toxicology and Applied PharmacologyElsevier

Published: Sep 1, 2005

References

  • Phosphatidylserine exposure during apoptosis is a cell-type-specific event and does not correlate with plasma membrane phospholipid scramblase expression
    Fadeel, B.; Gleiss, B.; Hogstrand, K.; Chandra, J.; Wiedmer, T.; Sims, P.J.; Henter, J.I.; Orrenius, S.; Samali, A.
  • Arsenite induces apoptosis via a direct effect on the mitochondrial permeability transition pore
    Larochette, N.; Decaudin, D.; Jacotot, E.; Brenner, C.; Marzo, I.; Santos, A.S.; Zamzami, N.; Xie, Z.; Reed, J.; Kroemer, G.
  • Mechanisms of action of arsenic trioxide
    Miller, W.H.; Schipper, H.M.; Lee, J.S.; Singer, J.; Waxman, S.
  • Mitochondrial regulation of apoptotic cell death
    Orrenius, S.

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