Junsheng Chen, Megan C. Yap, Arthur Bassot, Danielle M. Pascual, Tadashi Makio, Jannik Zimmermann, Heather Mast, Rakesh Bhat, Samuel G. Fleury, Yuxiang Fan, Adriana Zardini Buzatto, Jack Moore, Klaus Ballanyi, Liang Li, Michael Overduin, M. Joanne Lemieux, Hélène Lemieux, Grazia M.S. Mancini, Bruce Morgan, Paul C. Marcogliese, Thomas Simmen
Thioredoxin-related transmembrane proteins (TMXs) of the endoplasmic reticulum (ER) determine not only redox conditions within the ER lumen but also the formation and function of ER-mitochondria membrane contact sites (ERMCS). The presence of cytosolic, reactive oxygen species (ROS)-derived redox nanodomains at ERMCS suggests TMXs could also control these. The prime candidate for such a function is TMX2, the sole TMX family protein with a cytosolic thioredoxin domain. Indeed, TMX2 controls the extent of ERMCS through interaction with outer mitochondrial membrane proteins, including TOM70. Assisted by cytosolic peroxiredoxins, TMX2 moderates the sulfenylation of the TOM70 C 206 residue. Thereby, TMX2 reduces mitochondrial Ca 2+ uptake and metabolism. Accordingly, mutation of the TMX2 gene in cells from a patient with a neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity (NEDMCMS) results in hyperactive mitochondria. In a fly in vivo NEDMCMS model, TMX2 knockdown manifests predominantly in glial cells, where it prevents seizure-like behavior.