Serena Germani, Andrew Tri Van Ho, Alessandro Cherubini, Ersilia Varone, Alexander Chernorudskiy, Giorgia Maria Renna, Stefano Fumagalli, Marco Gobbi, Jacopo Lucchetti, Marco Bolis, Luca Guarrera, Ilaria Craparotta, Giorgia Rastelli, Giorgia Piccoli, Cosimo de Napoli, Leonardo Nogara, Elena Poggio, Marisa Brini, Angela Cattaneo, Angela Bachi, Thomas Simmen, Tito Calì, Susana Quijano-Roy, Simona Boncompagni, Bert Blaauw, Ana Ferreiro, Ester Zito
Selenoprotein N (SEPN1) is a protein of the endoplasmic reticulum (ER) whose inherited defects originate SEPN1-related myopathy (SEPN1-RM). Here, we identify an interaction between SEPN1 and the ER-stress-induced oxidoreductase ERO1A. SEPN1 and ERO1A, both enriched in mitochondria-associated membranes (MAMs), are involved in the redox regulation of proteins. ERO1A depletion in SEPN1 knockout cells restores ER redox, re-equilibrates short-range MAMs, and rescues mitochondrial bioenergetics. ERO1A knockout in a mouse background of SEPN1 loss blunts ER stress and improves multiple MAM functions, including Ca2+ levels and bioenergetics, thus reversing diaphragmatic weakness...
February 19, 2024: Cell reports medicine