Figure 1.

The proposed six-state kinetic mechanism of Ca²⁺ transport into mitochondria via the Ca²⁺ uniporter. The uniporter is assumed to have two binding sites for Ca²⁺ and the Ca²⁺ is assumed to bind to the uniporter from either side of the IMM. The ionized free Ca²⁺ from the cytoplasmic (external) side of the IMM cooperatively binds to the unbound uniporter (T) (State 1) in two steps to form the complex $\text{T}{\text{Ca}}_{\text{e}}^{2+}{\text{Ca}}_{\text{e}}^{2+}$ (State 5) which then undergo conformal changes (or flips upside down) to form the complex ${\text{Ca}}_{\text{x}}^{2+}{\text{Ca}}_{\text{x}}^{2+}\text{T}$ (State 6). The complex ${\text{Ca}}_{\text{x}}^{2+}{\text{Ca}}_{\text{x}}^{2+}\text{T}$ in the matrix (internal) side of the IMM goes through the reverse process where it dissociates in two steps to form the unbound uniporter (T) and ionized free Ca²⁺. The model also assumes the cross-interactions between the uniporter, external Ca²⁺, and internal Ca²⁺ to form the intermediate complex ${\text{Ca}}_{\text{x}}^{2+}{\text{TCa}}_{\text{e}}^{2+}$ (dead end, State 4). The other two states of the uniporter are the bound uniporter $\text{T}{\text{Ca}}_{\text{e}}^{2+}$ (State 2) and ${\text{Ca}}_{\text{x}}^{2+}\text{T}$ (State 3). (K_1,e, K_1,x) and (K_2,e, K_2,x) are the two pairs of dissociation (binding) constants for the two step uniporter binding reactions with the external and internal Ca²⁺. The transport of Ca²⁺ via the Ca²⁺ uniporter is limited by the rate constants k_in and k_out which are dependent on the membrane potential ΔΨ.