Apoptosis represents a critical noninflammatory mechanism for cell clearance in both physiological and pathological contexts, precisely regulated through the balance between proapoptotic and antiapoptotic signaling. Three well-characterized apoptotic pathways have been identified: (1) the intrinsic (mitochondria-mediated) pathway, (2) the extrinsic (death receptor-mediated) pathway, and (3) the endoplasmic reticulum (ER)-stress pathway. These processes are coordinated through the mitochondria-associated ER membrane (MAMs), which serves as a vital coupling platform between mitochondria and the ER. MAMs play pivotal roles in maintaining Ca²⁺ homeostasis and regulating apoptosis through dynamic alterations in architecture (e.g., gap width, contact number) that influence Ca²⁺ trafficking and tethering protein expression. Key protein complexes localized at MAMs (including the IP3Rs-Grp75-VDAC1 complex, Mfn1/Mfn2 complex, and PTPIP51-containing complex) regulate apoptosis through three primary mechanisms: Ca²⁺ homeostasis maintenance, lipid synthesis and transport, and mitochondrial morphology and dynamics. Furthermore, MAMs-mediated mitochondrial dynamics, particularly mitochondrial fission and cristae remodeling, contribute to apoptosis by facilitating Bax/Drp1 dimerization. This review systematically examines: how MAMs' structural dynamics influence Ca²⁺ signaling and tethering protein expression, the roles of MAMs-tethered proteins and their regulators in Ca²⁺ homeostasis, lipid metabolism, and mitochondrial dynamics, and the impact of mitochondrial dynamics on Bax/Drp1 dimerization during apoptosis.
Keywords: Bcl‐2 family proteins; apoptosis; mitochondrial dynamics; mitochondria‐associated ER; tether proteins.
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