Mathematical Modelling of Superoxide Generation with the bc₁ Complex of Mitochondria

O. V. Demin^1*, H. V. Westerhoff^2,3, and B. N. Kholodenko^1,2

¹Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119899 Russia; fax: (095) 939-3181; E-mail: bkhol@energ.genebee.msu.su

²Department of Microbial Physiology, Vrije Universiteit, De Boelelaan 1087, 1081 HV, Amsterdam, The Netherlands

³Slater Institute, BioCentrum Amsterdam, University of Amsterdam, The Netherlands

^* To whom correspondence should be addressed.

Received July 14, 1997; Revision received February 3, 1998

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It is widely believed that direct nonenzymatic semiquinone oxidation with oxygen is one of the sources of superoxide in mitochondria. In the present work we developed a mathematical model of coupled functioning of the bc₁ complex and ATP producing processes that allows one to obtain the dependence of superoxide production rate on membrane potential (DeltaPsi). Assuming that electron transfer between hemes of cytochrome b is the main electrogenic step of the Q-cycle, we found that rate of superoxide production increased dramatically with increase in DeltaPsi in the range from 170 to 200 mV. This explains experimental observation of a dramatic decrease in the superoxide production with decrease in DeltaPsi in the range from 200 to 170 mV. Generation of superoxide can be diminished with the inhibition of the electron supply to the Q-cycle, with decrease in external potassium, or increase in external inorganic phosphate level.

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KEY WORDS: mathematical model, mitochondria, superoxide radicals

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