TY - JOUR
T1 - The ER thioredoxin-related transmembrane protein TMX2 controls redox-mediated tethering of ER-mitochondria contacts
AU - Chen, Junsheng
AU - Yap, Megan C.
AU - Bassot, Arthur
AU - Pascual, Danielle M.
AU - Makio, Tadashi
AU - Zimmermann, Jannik
AU - Mast, Heather
AU - Bhat, Rakesh
AU - Fleury, Samuel G.
AU - Fan, Yuxiang
AU - Buzatto, Adriana Zardini
AU - Moore, Jack
AU - Ballanyi, Klaus
AU - Li, Liang
AU - Overduin, Michael
AU - Lemieux, M. Joanne
AU - Lemieux, Hélène
AU - Mancini, Grazia M.S.
AU - Morgan, Bruce
AU - Marcogliese, Paul C.
AU - Simmen, Thomas
N1 - Publisher Copyright:
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2025/11/25
Y1 - 2025/11/25
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105023545667
U2 - 10.1016/j.celrep.2025.116486
DO - 10.1016/j.celrep.2025.116486
M3 - Article
C2 - 41175374
AN - SCOPUS:105023545667
SN - 2211-1247
VL - 44
JO - Cell Reports
JF - Cell Reports
IS - 11
M1 - 116486
ER -