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Consequential modulation of mitochondrial K+- and H+-driven ATP synthase activity under excess cytoplasmic Na+ and oxidative stress mimicking heart failure: Modeling studiesстатья
Дата последнего поиска статьи во внешних источниках: 19 июня 2024 г.
- Авторы: Cortassa Sonya C., Aon Miguel A., Juhaszova Magdalena, Zorov Dmitry B., Sollott Steven J.
- Журнал: Biophysical Journal
- Том: 122
- Номер: 3
- Год издания: 2023
- Издательство: Biophysical Society
- Местоположение издательства: United States
- Первая страница: 96A
- DOI: 10.1016/j.bpj.2022.11.715
- Аннотация: Previously we demonstrated that mitochondrial ATP synthesis by F1Fo ATP synthase can be driven by K+ and H+ while regulating matrix volume and energy supply-demand matching under normal physiological conditions. In this new scenario, under conditions prevalent during heart failure such as Na+ accumulation and oxidized redox, we explored computationally the bioenergetic impact of mitochondrial Ca2+ levels and redox status on K+ transport and ATP synthesis. We utilized a computational model of mitochondrial function encompassing TCA cycle, oxidative phosphorylation (OxPhos), ionic transport, ROS production and ROS scavenging. Simulations were performed at increasing cytoplasmic Na+ concentrations (Nai) as means of changing mitochondrial Ca2+ in oxidized or reduced redox environments. The simulation protocol comprised consecutive pulses of increasing concentrations of ADP and cytoplasmic Ca2+ (ADP-Ca pulses). Under oxidizing redox environment, mitochondrial membrane potential (ΔΨm), matrix K+ and Ca2+ exhibit maladaptively decreased magnitudes as a function of Nai, both during baseline state 4 (absence of ADP) as well as following ADP-Ca pulses. In contrast, under reduced vs oxidized redox conditions, these variables exhibit adaptively larger transient amplitudes following the ADP-Ca pulses. OxPhos fluxes under state 4 were similar regardless of the redox state. However, during the successive ADP-Ca pulses, the lower the Nai the larger the increase in respiration, K+ uptake, and total ATP synthesis fluxes both under oxidized and reduced redox conditions. Also, at the lowest Nai, respiration can reach a 60% larger flux at the same ADP-Ca under reduced vs oxidized conditions. The simulation results predict that under heart failure conditions, the interplay between the cardiac redox status and cytoplasmic Na+ concentration significantly influences the mitochondrial energetic response, as assessed by ATP supply and degree of oxidative stress.
- Добавил в систему: Зоров Дмитрий Бориcович