Figure 1.

MERCS in health and in AD. In healthy controls (upper part of the figure), different functions of MERCS are integrated to maintain cell homeostasis. The IP3Rs-Grp75-VDAC1 complex together with the MCU complex allows the entry of Ca²⁺ into mitochondria, where it can boost the TCA cycle, inducing ATP production. This complex, together with Mfns and the PTPIP51 and VAPB pair, can modulate the connectivity between the ER and mitochondria. Additionally, the formation of the isolation membrane, which is the precursor to the mature autophagosome, originates at MERCS and can be modulated by the function or ultrastructure of MERCS. Similarly, Aβ also originates in this subcellular region. In AD, the connectivity between the ER and mitochondria is enhanced and Ca²⁺ inside mitochondria is upregulated, and mitochondrial dysfunction, activation of the UPR^ER and UPR^mt, impaired autophagosome maturation and changes in Aβ levels are increased, which can ultimately lead to cell death. Different colours correspond to proteins involved in different cellular processes and faded colours as well as dashed lines represent the downregulation of the process or protein level/function. mPS2 represents PS2 with a FAD mutation.