Mitochondria-ER contact sites in neurodegeneration: a homeostatic hub linking metabolic stress, neuroinflammation, and therapeutic opportunities

Abstract

Neurodegenerative diseases (NDDs) involve self-amplifying interactions among proteotoxic stress, mitochondrial dysfunction, and neuroinflammation. Emerging evidence increasingly implicates mitochondria-endoplasmic reticulum contact sites (MERCs) as dynamic homeostatic hubs that may link these processes, but their causal status in human NDDs remains incompletely established. This review synthesizes evidence connecting MERCs biology with NDD-associated mitochondrial stress, Ca 2+ dysregulation, lipid remodeling, redox signaling, and inflammatory cell death. We frame the MERCs-centered model as a working, testable hypothesis and use Eleutherococcus senticosus as a case study for candidate phytochemical modulation of MERCs-associated stress pathways. Available cellular, animal, and human-tissue evidence suggests that altered MERCs structure and function can contribute to mitochondrial Ca 2+ overload, reactive oxygen species (ROS) generation, mtDNA/DAMP release, and NLRP3 inflammasome activation. Natural products may influence this network indirectly through mitochondrial metabolism, membrane composition, ER stress, redox buffering, and regulated Ca 2+ handling, but direct proof of MERCs restoration remains limited. MERCs should be viewed as a convergent homeostatic hub and therapeutic hypothesis rather than a validated upstream cause of NDDs. Future studies should distinguish structural contact-site changes from functional correction and should test phytochemical candidates using direct MERCs proximity, flux, lipidomics, and bioenergetic assays.