Mitochondria-associated membranes (MAMs) are essential for cellular homeostasis. MAMs
are specialized contact sites located between the endoplasmic reticulum (ER) and mitochondria
and control apoptotic pathways, lipid metabolism, autophagy initiation, and calcium
signaling, processes critical to the survival and function of neurons. Although this
area of membrane biology remains understudied, increasing evidence links MAM dysfunction
to the etiology of major neurodegenerative diseases, such as Alzheimer’s disease,
Parkinson’s disease, and amyotrophic lateral sclerosis (ALS). MAMs consist of a network
of protein complexes that mediate molecular exchange and ER–mitochondria tethering.
MAMs regulate lipid flow in the brain, including phosphatidylserine and cholesterol;
disruption of this process causes membrane instability and impaired synaptic function.
Inositol 1,4,5-trisphosphate receptor—voltage-dependent anion channel 1 (IP3R-VDAC1)
interactions at MAMs maintain calcium homeostasis, which is required for mitochondria
to produce ATP; dysregulation promotes oxidative stress and neuronal death. An effective
therapeutic approach for altering neurodegenerative processes is to restore the functional
integrity of MAMs. Improving cell-to-cell interactions and modulating MAM-associated
proteins may contribute to the restoration of calcium homeostasis and lipid metabolism,
both of which are key for neuronal protection. MAMs significantly contribute to the
progression of neurodegenerative diseases, making them promising targets for future
therapeutic research. This review emphasizes the increasing importance of MAMs in
the study of neurodegeneration and their potential as novel targets for membrane-based
therapeutic interventions.
