Presenilin-2 modulation of ER-mitochondria interactions

Figures & data

Figure 1 ER-mitochondria juxtaposition and high Ca²⁺ microdomains on the cytosolic surface of OMM in SH-SY5Y cells. Cells were transfected with cDNAs coding for a FAD-PS2 mutant (PS2-T122R, B) or void vector (Control, A), together with those coding for a red mitochondrial and a green ER markers (mit-RFP and ER-GFP, respectively; upper cell in each part), in order to visualize ER-mitochondria juxtaposition sites (yellow pixels); increased number of interactions is observed in FAD-PS2 expressing cells. Alternatively, cells were transfected with cDNAs coding for a FAD-PS2 mutant (PS2-T122R, B) or void vector (Control, A) and the cameleon Ca²⁺ probe N33-D1cpv, targeted to the OMM,15 and then analyzed to detect the generation of high Ca²⁺ microdomains on the cytosolic surface of OMM (yellow-to-red spikes) upon ER Ca²⁺ release induced by bradykinin (lower cell in each part). At a similar average cytosolic Ca²⁺ rise, higher and more abundant Ca²⁺ microdomains are generated close to the OMM in the FAD-PS2 expressing cell compared to the control one. See reference 13 for details.

Figure 2 Model depicting the possible effects of FAD-PS2 mutations on ER-mitochondria interactions and Ca²⁺ cross-talk. In physiological condition (A), mitochondria receive constant Ca²⁺ signals from ER that ensure their proper activity.30 Expression of FAD-PS2 mutants (B and C) decreases [Ca²⁺]_ER27,28 and recruits mitochondria closer to ER Ca²⁺ releasing sites.13 As a consequence, closer ER-mitochondria juxtaposition may compensate [Ca²⁺]_ER reduction allowing mitochondria to receive appropriate Ca²⁺ signals that drive AT P production (B); alternatively, closer ER-mitochondria juxtaposition may expose mitochondria to excessive Ca²⁺ stimulation, triggering the apoptotic cascade29 by mitochondria Ca²⁺ overload, outer membrane permeabilization and release of pro-apoptotic factors (C).

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