Consequential modulation of mitochondrial K+- and H+-driven ATP synthase activity under excess cytoplasmic NA+ and oxidative stress mimicking heart failure: Modeling studies
Biophysical Journal(2023)
摘要
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.
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关键词
atp,oxidative stress,heart failure
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