Mitochondrial depolarization promotes calcium alternans: Mechanistic insights from a ventricular myocyte model

Figures

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  Fig 1. Mitochondrial depolarization promotes Ca2+ alternans. A. Time traces of membrane potential V, whole-cell averaged cytosolic Ca2+ concentration [Ca2+]¯i, SR Ca2+concentration [Ca2+]¯JSR, SERCA uptake flux, SR Ca2+ release flux via RyRs, mitochondrial free Ca2+ [Ca2+]¯m, open probability of mPTP P¯mPTP, mitochondrial membrane potential −Δψ¯, cytosolic ROS concentration [ROS]¯cyt, cytosolic CaMKII activation [CaMKII]¯act, cytosolic ATP concentration [ATP]¯cyt for normal control (αmPTP = 1) in black and mitochondrial depolarization (αmPTP = 60) conditions in red, respectively. PCL is 500 ms. Note that the horizontal bar above each variable means that the quantity is an averaged value over all the CRUs or mitochondria within the myocyte. B. Bifurcation diagrams of peak values of [Ca2+]¯i in the last two consecutive beats vs. PCL for control (black) and mitochondrial-depolarization (red) cases.

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  Fig 2. Effect of cytosolic ROS signaling on the genesis of Ca2+ alternans. A. Bifurcation diagram of peak values of Ca2+ transients vs. αmPTP for free-running ROS (black) and fixed ROS = 0.1 μM (red), respectively. B. Bifurcation diagram of peak values of Ca2+ transient vs. αmPTP with free-running ROS, but the redox effect of ROS only exerted on RyRs (green) or SERCA (blue), respectively. The PCL is 500 ms. The total simulation time for each simulation is 30 sec.

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  Fig 3. MCU upregulation promotes Ca2+ alternans through Ca2+- dependent opening of mPTP. Dependence of Ca2+ alternan amplitude Δ[Ca2+]¯i on αMCU and αmPTP. Δ[Ca2+]¯i is calculated as the difference between the last two Ca2+ transient peaks in a simulation of 30 sec. PCL = 500 ms.

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  Fig 4. Effect of CaMKII activation on the genesis of the Ca2+ alternans. Bifurcation diagrams of peak values of Ca2+ transients in the last two beats vs. αmPTP for clamped CaMKII activation level 1% (A), 10% (B) and 30% (C), respectively. PCL = 500 ms.

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  Fig 5. Effect of ATP on the genesis of Ca2+ alternans. Bifurcation diagrams of peak values of Ca2+ transients in the last two beats vs. clamped whole-cell average ATP level in the cytosol. αmPTP = 30. The PCL = 500 ms.