Endoplasmic reticulum – Mitochondrial crosstalk at MAMs: Shaping cancer metabolism and cell death decisions

Mitochondria-associated membranes (MAMs) are specialized contact sites between the endoplasmic reticulum (ER) and mitochondria that coordinate calcium signaling, lipid transfer, metabolic regulation, and cell fate decisions. Growing evidence indicates that MAMs act as dynamic signaling hubs integrating ER stress responses with mitochondrial metabolism. In cancer, where chronic ER stress and metabolic rewiring are hallmarks, tumor cells exploit MAM plasticity to sustain bioenergetic fitness, promote stress tolerance, and evade apoptosis. Remodeling of ER-mitochondrial contacts alters calcium flux, autophagy, and apoptotic thresholds, thereby supporting tumor progression and therapy resistance. Conversely, disruption of MAM-mediated signaling can overwhelm adaptive stress responses and restore cell death pathways. This mini-review summarizes current understanding of MAM biology, highlights their role in cancer metabolism and stress adaptation, and discusses emerging experimental approaches and therapeutic opportunities targeting ER-mitochondrial crosstalk.