Membrane contact sites harbor a distinct set of proteins with varying biological functions, thereby emerging as hubs for localized signaling nanodomains underlying adequate cell function. Here, we will focus on mitochondria-associated endoplasmic reticulum membranes (MAMs), which serve as hotspots for Ca2+ signaling, redox regulation, lipid exchange, mitochondrial quality and unfolded protein response pathway. A network of MAM-resident proteins contributes to the structural integrity and adequate function of MAMs. Beyond endoplasmic reticulum (ER)-mitochondrial tethering proteins, MAMs contain several multi-protein complexes that mediate the transfer of or are influenced by Ca2+, reactive oxygen species and lipids. Particularly, IP3 receptors, intracellular Ca2+-release channels, and Sigma-1 receptors (S1Rs), ligand-operated chaperones, serve as important platforms that recruit different accessory proteins and intersect with these local signaling processes. Furthermore, many of these proteins are directly implicated in pathophysiological conditions, where their dysregulation or mutation is not only causing diseases such as cancer and neurodegeneration, but also rare genetic diseases, for example familial Parkinson's disease (PINK1, Parkin, DJ-1), familial Amyotrophic lateral sclerosis (TDP43), Wolfram syndrome1/2 (WFS1 and CISD2), Harel-Yoon syndrome (ATAD3A). In this review, we will discuss the current state-of-the-art regarding the molecular components, protein platforms and signaling networks underlying MAM integrity and function in cell function and how their dysregulation impacts MAMs, thereby driving pathogenesis and/or impacting disease burden. We will highlight how these insights can generate novel, potentially therapeutically relevant, strategies to tackle disease outcomes by improving the integrity of MAMs and the signaling processes occurring at these membrane contact sites.

Cellular and Molecular Neuropharmacology Lab Department of Biology and Biotechnology L Spallanzani University of Pavia Pavia Italy

Department of Cellular Cardiology Institute of Experimental Endocrinology Biomedical Research Center Slovak Academy of Sciences Bratislava Slovakia

Department of Experimental Biology Faculty of Science Masaryk University Brno Czech Republic; International Clinical Research Center St Anne's University Hospital Brno Czech Republic

Department of Genetics Cancer Research Institute Biomedical Research Center Slovak Academy of Sciences Bratislava Slovakia

Department of Genetics Hadassah Medical Center Jerusalem Israel

Department of Genetics Hadassah Medical Center Jerusalem Israel; Faculty of Medicine Hebrew University Medical Center Jerusalem Israel

Department of Metabolic Diseases Institute of Experimental Endocrinology Biomedical Research Center Slovak Academy of Sciences Bratislava Slovakia

Department of Pharmacology Institute of Biomedicine and Translational Medicine Faculty of Medicine University of Tartu Tartu Estonia

KU Leuven Cellular and Molecular Medicine Laboratory of Molecular and Cellular Signaling Campus Gasthuisberg ON 1 Leuven Belgium

Latvian Institute of Organic Synthesis Riga Latvia

MMDN University of Montpellier EPHE INSERM Montpellier France

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