Ascorbate and Low Concentrations of FeSO₄ Induce Ca²⁺-Dependent Pore in Rat Liver Mitochondria

I. V. Brailovskaya¹, A. A. Starkov², and E. N. Mokhova^2*

¹Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, pr. M. Toreza 44, St. Petersburg, 194223 Russia

²Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119899 Russia; fax: (095) 939-0338; E-mail: mokhova@genebee.msu.su

^* To whom correspondence should be addressed.

Received January 24, 2001; Revision received April 20, 2001

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Oxidative stress is one of the most frequent causes of tissue and cell injury in various pathologies. The molecular mechanism of mitochondrial damage under conditions of oxidative stress induced in vitro with low concentrations of FeSO₄ and ascorbate (vitamin C) was studied. FeSO₄ (1-4 µM) added to rat liver mitochondria that were incubated in the presence of 2.3 mM ascorbate induced (with a certain delay) a decrease in membrane potential and high-amplitude swelling. It also significantly decreased the ability of mitochondria to accumulate exogenous Ca²⁺. All the effects of FeSO₄ + ascorbate were essentially prevented by cyclosporin A, a specific inhibitor of the mitochondrial Ca²⁺-dependent pore (also known as the mitochondrial permeability transition). EGTA restored the membrane potential of mitochondria de-energized with FeSO₄ + ascorbate. We hypothesize that oxidative stress induced in vitro with FeSO₄ and millimolar concentrations of ascorbate damages mitochondria by inducing the cyclosporin A-sensitive Ca²⁺-dependent pore in the inner mitochondrial membrane.

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KEY WORDS: vitamin C, ferrous ion, oxidative stress, permeability transition, cyclosporin A, liver mitochondria

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