It is well established that cobalt mediates the occurrence of oxidative stress which contributes to cell toxicity and death. However, the mechanisms of these effects are not fully understood. This investigation aimed at establishing if cobalt acts as an inducer of mitochondrial-mediated apoptosis and at clarifying the mechanism of this process. Cobalt, in the ionized species Co2+, is able to induce the phenomenon of mitochondrial permeability transition (MPT) in rat liver mitochondria (RLM) with the opening of the transition pore. In fact, Co2+ induces mitochondrial swelling, which is prevented by cyclosporin A and other typical MPT inhibitors such as Ca2+ transport inhibitors and bongkrekic acid, as well as anti-oxidant agents. In parallel with mitochondrial swelling, Co2+ also induces the collapse of electrical membrane potential. However in this case, cyclosporine A and the other MPT inhibitors (except ruthenium red and EGTA) only partially prevent ΔΨ drop, suggesting that Co2+ also has a proton leakage effect on the inner mitochondrial membrane. MPT induction is due to oxidative stress, as a result of generation by Co2+ of the highly damaging hydroxyl radical, with the oxidation of sulfhydryl groups, glutathione and pyridine nucleotides. Co2+ also induces the release of the pro-apoptotic factors, cytochrome c and AIF. Incubation of rat hepatocyte primary cultures with Co2+ results in apoptosis induction with caspase activation and increased level of expression of HIF-1α. All these observations allow us to state that, in the presence of calcium, Co2+ is an inducer of apoptosis triggered by mitochondrial oxidative stress.

Cobalt induces oxidative stress in isolated liver mitochondria responsible for permeability transition and intrinsic apoptosis in hepatocyte primary cultures.

COMPAGNONE, Alessandra;BANDINO, Andrea;COLOMBATTO, Sebastiano;GRILLO, Maria Angelica;
2009

Abstract

It is well established that cobalt mediates the occurrence of oxidative stress which contributes to cell toxicity and death. However, the mechanisms of these effects are not fully understood. This investigation aimed at establishing if cobalt acts as an inducer of mitochondrial-mediated apoptosis and at clarifying the mechanism of this process. Cobalt, in the ionized species Co2+, is able to induce the phenomenon of mitochondrial permeability transition (MPT) in rat liver mitochondria (RLM) with the opening of the transition pore. In fact, Co2+ induces mitochondrial swelling, which is prevented by cyclosporin A and other typical MPT inhibitors such as Ca2+ transport inhibitors and bongkrekic acid, as well as anti-oxidant agents. In parallel with mitochondrial swelling, Co2+ also induces the collapse of electrical membrane potential. However in this case, cyclosporine A and the other MPT inhibitors (except ruthenium red and EGTA) only partially prevent ΔΨ drop, suggesting that Co2+ also has a proton leakage effect on the inner mitochondrial membrane. MPT induction is due to oxidative stress, as a result of generation by Co2+ of the highly damaging hydroxyl radical, with the oxidation of sulfhydryl groups, glutathione and pyridine nucleotides. Co2+ also induces the release of the pro-apoptotic factors, cytochrome c and AIF. Incubation of rat hepatocyte primary cultures with Co2+ results in apoptosis induction with caspase activation and increased level of expression of HIF-1α. All these observations allow us to state that, in the presence of calcium, Co2+ is an inducer of apoptosis triggered by mitochondrial oxidative stress.
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http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TCH-4T3VRD8-1&_user=525216&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000026382&_version=1&_urlVersion=0&_userid=525216&md5=a6d9e29f144a31db99ca5b8ac03f6f97
Isolated liver mitochondria; Hepatocytes primary cultures; Cobalt; Oxidative stress; Apoptosis
Battaglia V; Compagnone A; Bandino A; Bragadin M; Rossi CA; Zanetti F; Colombatto S; Grillo MA; Toninello A.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/55341
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