The ER thioredoxin-related transmembrane protein TMX2 controls redox-mediated tethering of ER-mitochondria contacts

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 C₂₀₆ residue. Thereby, TMX2 reduces mitochondrial Ca²⁺ 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.