Control of mitochondria-associated endoplasmic reticulum membranes by protein S-palmitoylation: Novel therapeutic targets for neurodegenerative diseases

Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic coupling structures between mitochondria and the endoplasmic reticulum (ER). As a new subcellular structure, MAMs combine the two critical organelle functions. Mitochondria and the ER could regulate each other via MAMs. MAMs are involved in calcium (Ca2+) homeostasis, autophagy, ER stress, lipid metabolism, etc. Researchers have found that MAMs are closely related to metabolic syndrome and neurodegenerative diseases (NDs). The formation of MAMs and their functions depend on specific proteins. Numerous protein enrichments, such as the IP3R-Grp75-VDAC complex, constitute MAMs. The changes in these proteins govern the interaction between mitochondria and the ER; they also affect the biological functions of MAMs. S-palmitoylation is a reversible protein post-translational modification (PTM) that mainly occurs on protein cysteine residues. More and more studies have shown that the S-palmitoylation of proteins is closely related to their membrane localization. Here, we first briefly describe the composition and function of MAMs, reviewing the component and biological roles of MAMs mediated by S-palmitoylation, elaborating on S-palmitoylated proteins in Ca2+ flux, lipid rafts, and so on. We try to provide new insight into the molecular basis of MAMs-related diseases, mainly NDs. Finally, we propose potential drug compounds targeting S-palmitoylation. [Display omitted] •S-palmitoylation is strongly associated with the localization of proteins in MAMs.•S-palmitoylation of regulators in MAMs is involved in Ca2+ flux, lipid rafts, and mitochondrial dynamics.•S-palmitoylation-controlled MAMs could be new targets for neurodegenerative diseases.