bistability of mitochondrial respiration underlies paradoxical reactive oxygen species generation induced by anoxia双稳态的线粒体呼吸构成矛盾的活性氧生成缺氧引起的.pdf

Bistability of Mitochondrial Respiration Underlies Paradoxical Reactive Oxygen Species Generation Induced by Anoxia 1,2,3 4 4 4 2 Vitaly A. Selivanov , Tatyana V. Votyakova *, Jennifer A. Zeak , Massimo Trucco , Josep Roca , Marta Cascante1* 1 Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Institut de Biomedicina at Universitat de Barcelona IBUB and IDIBAPS Hospital Clinic, Barcelona, ´ Catalunya, Spain, 2 Hospital Clınic, IDIBAPS, CIBERES; Universitat de Barcelona, Barcelona, Catalunya, Spain, 3 A.N.Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia, 4 Department of Pediatrics, The University of Pittsburgh School of Medicine and The Children’s Hospital of Pittsburgh, Diabetes Institute, Pittsburgh, Pennsylvania, United States of America Abstract Increased production of reactive oxygen species (ROS) in mitochondria underlies major systemic diseases, and this clinical problem stimulates a great scientific interest in the mechanism of ROS generation. However, the mechanism of hypoxia- induced change in ROS production is not fully understood. To mathematically analyze this mechanism in details, taking into consideration all the possible redox states formed in the process of electron transport, even for respiratory complex III, a system of hundreds of differential equations must be constructed. Aimed to facilitate such tasks, we developed a new methodology of modeling, which resides in the automated construction of large sets of differential equations. The detailed modeling of electron transport in mitochondria allowed for the identification of two steady state modes of operation (bistability) of respirat