Potential Role of Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs) Abnormalities in Epileptogenesis: Multimodal Mechanisms and Therapeutic Targets.

Epilepsy is a prevalent neurological disorder characterized by an incompletely understood etiology and a substantial unmet therapeutic need, particularly for drug-resistant forms. This review examines the potential role of mitochondria-associated endoplasmic reticulum membranes (MAMs) as emerging signaling hubs in epileptogenesis. We systematically analyze how MAMs regulate core cellular processes-including calcium signaling, lipid metabolism, mitochondrial dynamics, autophagy, and oxidative stress-and how dysregulation of these processes may contribute to seizure initiation and progression. Furthermore, we evaluate existing interventions, such as phytotherapeutics and the ketogenic diet, from the perspective of modulation of MAMs. The review also highlights novel strategies targeting MAMs, including small-molecule approaches, nanodelivery systems, and neuromodulation technologies, which offer promising avenues for precise therapeutic intervention. By consolidating current molecular and genetic evidence, we identify MAMs as a critical hub in epilepsy and propose that targeting their integrity and function may represent a strategy to overcome drug resistance and modify disease progression. By integrating current knowledge of MAMs biology with epilepsy pathophysiology, this work provides a mechanistic framework to guide future research. It offers insights for the development of targeted molecular therapies for epilepsy.