Priority Research Paper Volume 9, Issue 3 pp 627—649

Figure 9. Hypothetical model of Fus1 activities in mitochondria. (A) At steady-state or low [Ca²⁺]c levels, Fus1 has a dual effect on [Ca²⁺]m: it (1) stimulates mitochondrial Na⁺/Ca²⁺ exchanger (mNCX) that is responsible for efflux of Ca²⁺ from the mitochondrial matrix in exchange for Na⁺ from the intermembrane space, and (2) inhibits mitochondrial Ca²⁺ uptake (mtCU) mechanisms (e.g., MCU). These data allow us to consider Fus1 as a gatekeeper for mtCU, which is potentially able to filter out Ca²⁺ signals with inappropriate characteristics (e.g., low-amplitude, short, etc.). (B) Binding of Ca²⁺ (dark circle inside Fus1) to Fus1 after [Ca²⁺]c elevation leads to a release of myristoil residue (purple tail) and its anchoring to the mitochondrial matrix membrane. It is accompanied by mNCX inhibition and mtCU activation. The latter has an ability of self-inhibition by Ca²⁺ (negative feedback loop), the mechanism that is probably suppressed by Fus1 thereby letting mtCU to gain inward Ca²⁺ currents in a dynamic mode demonstrating a feature of a positive feedback loop. (C) In the absence of Fus1, mitochondria accumulate more Ca²⁺ at steady state or at the beginning of a Ca²⁺ response due to the lack of the gatekeeping function of Fus1 and decreased activity of mNCX. (D) During the dynamic development of a Ca²⁺ response, mtCU in mitochondria lacking Fus1 is auto-inhibited by Ca²⁺ while mNCX is activated due to the lack of Fus1 suppressive activities, which results in an elevated efflux of Ca²⁺ from mitochondria.