Modulation of Mitochondria–Endoplasmic Reticulum Contacts (MERCs) by Small Molecules as a New Strategy for Restoring Lipid Metabolism in an Amyotrophic Lateral Sclerosis Model
Mikel Etxebeste-Mitxeltorena, Hector Flores‐Romero, Sandra Ramos-Inza, Esther Masiá, Maria Nenchova, Jorge Montesinos, Loreto Martínez‐González, Gracia Porras, Mar Orzáez, Marı́a J. Vicent, Carmen Gil, Estela Área-Gómez, Ana J. García‐Sáez, Ana Martı́nez
Abstract
High Resolution Image Download MS PowerPoint Slide Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without effective treatment. The progressive motoneuron death in ALS is associated with alterations in lipid metabolism. As its regulation occurs in mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), modulation of mitochondria-ER contacts (MERCs) is emerging as a crucial factor in MAM formation and lipid metabolism control. Using the MERLIN biosensor in a high-throughput screening within the EU-OPENSCREEN ERIC, we discovered small molecules that increase MERCs in HCT116 cells, enhancing their ability to uptake cholesterol. We demonstrated that cholesterol trafficking is decreased in an ALS patient-derived cell model, and this trafficking is restored after treatment with the discovered MERC modulator 24 . Electron microscopy revealed that treatment with compound 24 increases MERCs, promotes lipid droplet formation, and restores mitochondrial cristae. Overall, the brain-permeable MERC modulator, compound 24, may serve as a valuable pharmacological tool for studying MAM function and holds potential for in vivo studies in ALS and other MAM dysfunction diseases.