Significance: In all cells, the endoplasmic reticulum (ER) and mitochondria are physically connected to form junctions termed mitochondria-associated membranes (MAMs). This subcellular compartment is under intense investigation because it represents a "hot spot" for the intracellular signaling of important pathways, including the synthesis of cholesterol and phospholipids, calcium homeostasis, and reactive oxygen species (ROS) generation and activity. Recent Advances: The advanced methods currently used to study this fascinating intracellular microdomain in detail have enabled the identification of the molecular composition of MAMs and their involvement within different physiopathological contexts. Critical Issues: Here, we review the knowledge regarding (i) MAMs composition in terms of protein composition, (ii) the relationship between MAMs and ROS, (iii) the involvement of MAMs in cell death programs with particular emphasis within the tumor context, (iv) the emerging role of MAMs during inflammation, and (v) the key role of MAMs alterations in selected neurological disorders. Future Directions: Whether alterations in MAMs represent a response to the disease pathogenesis or directly contribute to the disease has not yet been unequivocally established. In any case, the signaling at the MAMs represents a promising pharmacological target for several important human diseases.
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