Figure 11.

Mechanistic insights from the computer model into the roles of mitochondrial Ca²⁺ handling in the genesis of early afterdepolarizations (EADs). A through C, Ca²⁺ concentrations in different compartments of the cell model vs the strength of mitochondrial Ca²⁺ uniporter (MCU), showing bistability. The simulations were performed as follows. We first started the simulations from the normal control MCU activity (α_MCU=1) and increased α_MCU gradually to 35, as indicated by the blue arrows (B). The system switches from no EADs (also low Ca²⁺ concentration states) to EADs (also high Ca²⁺ concentration states) at α_MCU≈30, at which the mitochondrial free Ca²⁺ reaches 136 nmol/L (open arrow). For each α_MCU, 50 beats were simulated for the cell to reach steady state before changing to a larger α_MCU. We then started the simulations in the same way but from a high MCU activity (α_MCU=35) to the normal control value (α_MCU=1), as indicated by the red arrow (B). The system switches from EADs to no EADs at α_MCU≈2.4. D. [Ca²⁺]_mito, [Ca²⁺]_i, [Ca²⁺]_SR, I_NCX, I_{C a,L}, and V vs time from 2 simulations for α_MCU=5. In the first simulation (blue traces), the mitochondrial Ca²⁺ is free running (unclamped), and the cell is in the low Ca²⁺ state without EADs. In the second simulation (red traces), [Ca²⁺]_mito is suddenly elevated to 200 nmol/L and held constant (clamped) for the rest of the simulation. 1, 2, and 3 mark the first 3 beats during the clamped phase. [Ca²⁺]_mito indicates mitochondrial Ca²⁺ concentration; [Ca²⁺]_i, intracellular Ca²⁺ concentration; [Ca²⁺]_SR, SR Ca²⁺ concentration; INCX, NCX current; I_caL, L‐type Ca²⁺ current; V, membrane potential.