Ca2+ pushes and pulls energetics to maintain ATP balance in atrial cells: computational insights

Figures

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  FIGURE 1. Schematic illustrations of excitation-contraction-energetics coupling. (A) The interplay between ionic channels and exchangers to the myofilaments, sarcoplasmic reticulum Ca2+ cycling proteins, and basal state ATP demand and the interplay between Krebs cycle proteins, pyruvate dehydrogenize, mitochondrial complexes, channels and exchangers with Ca2+ ions in atrial cells. (B) The interconnected signaling mediating the different models. Created with BioRender.com.

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  FIGURE 2. ATP supply in atrial cells. Respiration rates of isolated atrial cell suspensions (n = 5) electrically stimulated at 1, 2 and 3 Hz *p < 0.05 vs. 1 Hz.

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  FIGURE 3. ATP demand in atrial cells. (A) Relative ATP consumption by sarcoplasmic reticulum Ca2+ cycling proteins, myofilaments and membranal pumps on exposure to electrical stimulation at different frequencies. (B) Ca2+ uptake by the sarcoplasmic reticulum, (C) force and (D) intracellular Ca2+ in response to electrical stimulus at frequencies 1, 2 and 3 Hz. (E) t50 (50% decline time of the Ca2+ signal from the peak) and t90 (90% decline time of the Ca2+ signal from the peak) achieved at 1 Hz and 3 Hz electrical stimulus frequencies both in the experiments (n = 36) and the model.

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  FIGURE 4. Metabolic homeostasis is response to electrical stimulus. (A) Mitochondrial Ca2+, (B) FADH2 and (C) NADH concentrations and (D) oxygen consumption in response to electrical stimulus at frequencies of 1, 2 and 3 Hz. The average experimental results are shown by the dashed line. (E) Experimental results of flavoprotein fluorescence in isolated atrial cells in response to electrical stimulus at frequencies of 1, 2 and 3 Hz (n = 7). To quantify the dynamic range of the oxidized vs. reduced flavoprotein pool, 100 μmol/L 2,4-dinitrophenol (DNP); (maximum flavoprotein fluorescence) and 4 mmol/L NaCN (reduced flavoproteins; minimal fluorescence) were added at the end of the experiment. The results are presented as mean (black line) with standard error (gray area).

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  FIGURE 5. Oscillation of Krebs cycle protein concentrations. (A) Acetyl-CoA, (B) citrate, (C) isocitrate, (D) α-ketoglutarate, (E) succinyl-CoA, (F) succinate, (G) fumarate, (H) L-malate and (I) oxaloacetate concentrations in response to electrical stimulus at frequencies of 1, 2 and 3 Hz.

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  FIGURE 6. Push and pull mechanisms driven by Ca2+. (A) Oxygen consumption, (B) FADH2 concentration, (C) intracellular ATP and (D) mitochondrial ATP in response to electrical stimulus at frequencies of 1, 2 and 3 Hz. The model was tested without push and pull mechanisms driven by Ca2+, with only a Ca2+ push mechanism and with both push and pull mechanisms driven by Ca2+.

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  FIGURE 7. Flavoprotein homeostasis in atrial cells. Flavoprotein fluorescence in isolated atrial cells. The stimulus frequency was raised from 0.25 Hz to 2 Hz and then returned to 0.25 Hz (n = 4). Mean fluorescence is presented by a blue line and standard error by the light blue area around it. Note that the standard error increased towards the end of protocol, as the measurement of two of the cells was terminated before the end of the protocol due to technical issues.

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  FIGURE 8. Model prediction of metabolic homeostasis is response to electrical stimulus. (A) Mitochondrial Ca2+, (B) FADH2 concentration, (C) NADH concentration and (D) oxygen consumption in response to electrical stimulus frequency that was raised from 0.25 Hz to 2 Hz and then returned to 0.25 Hz. The model was tested without Ca2+ push and pull mechanisms, with only Ca2+ push mechanism and with both Ca2+ push and pull mechanisms.