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PreprintCited by 9Redox biology and oxidative stressMitochondrial Function and PathologyIon Channels and Receptors

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The ER Thioredoxin-Related Transmembrane Protein TMX2 Controls Redox-Mediated Tethering of ER-Mitochondria Contacts (ERMCS)

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Chen, Junsheng, Yap, Megan C., Bassot, Arthur, Pascual, Danielle M., Makio, Tadashi, Zimmermann, Jannik, Mast, Heather, Bhat, Rakesh, Fleury, Samuel G., Fan, Yuxiang, Buzatto, Adriana Zardini, Moore, Jack, Ballanyi, Klaus, Li, Liang, Overduin, Michael, Lemieux, M. Joanne, Lemieux, Hélène, Tan, Wen-Hann, Mancini, Grazia M.S., Morgan, Bruce, Marcogliese, Paul C., Simmen, Thomas·2024·Cell Reports
DOI 10.1101/2024.04.12.589228

Preprint — published as 10.1016/j.celrep.2025.116486

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Abstract

Summary: Thioredoxin-related transmembrane proteins (TMX) of the endoplasmic reticulum (ER) have emerged as key regulators of ER membrane properties. Within the ER lumen, TMX proteins and other ER redox enzymes determine oxidative conditions, which control the formation of ER-mitochondria membrane contacts (ERMCS) and determine their function. ERMCS exhibit cytoplasmic redox nanodomains, derived from ER and mitochondrial reactive oxygen species (ROS), whose mechanistic regulation is uncharacterized. Our research has identified the ER protein TMX2, which uses its unique cytosolic thioredoxin domain to prevent cytosolic sulfenylation of mitochondrial outer membrane proteins such as TOM70 through a functional interaction with peroxiredoxin-1 (PRDX1). By doing so, TMX2 interferes with the TOM70 ERMCS tethering function and reduces mitochondrial Ca 2+ flux and metabolism. Recently, TMX2 mutations have been identified to cause a neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity (NEDMCMS). Using TMX2-mutated NEDMCMS patient cells, we demonstrate that compromising TMX2 through mutation reproduces mitochondrial defects. In a fly in vivo model, TMX2 knockdown manifests predominantly in glial cells. Our results therefore provide important mechanistic insight into NEDMCMS and mechanistically link TMX2-mediated control of ERMCS to brain development and function. Graphical Abstract: The transmembrane thioredoxin-related TMX2 prevents TOM70 sulfenylation at ERMCS, thus maintaining normal mitochondria metabolism in wild-type cells. TMX2 knockout leads to TOM70 sulfenylation and tight ERMCS formation. This then increases ROS production, unbalances mitochondrial lipids, and relatively shifts OXPHOS electron supply to complex II.

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Metadata

Authors
Chen, J., Yap, M. C., Bassot, A., Pascual, D. M., Makio, T., Zimmermann, J., Mast, H., Bhat, R., Fleury, S. G., Fan, Y., Buzatto, A. Z., Moore, J., Ballanyi, K., Li, L., Overduin, M., Lemieux, M. J., Lemieux, H., Tan, W.-H., Mancini, G. M. S., Morgan, B., Marcogliese, P. C., & Simmen, T.
Affiliations
  • University of Alberta (CA)
  • Centre National de la Recherche Scientifique (FR)
  • Children's Hospital Research Institute of Manitoba (CA)
  • Saarland University (DE)
  • Boston Children's Hospital (US)
  • Erasmus MC (NL)
Corresponding author
Simmen, Thomas
ORCID
Venue
Cell Reports
Publisher
openRxiv
Published
2024-04-13
Volume
44
Issue
11
Pages
116486-116486
ISSN
2211-1247 (ISSN-L)
DOI
10.1101/2024.04.12.589228
OpenAlex
W4415718086
Cited by
9
References
1
Citations by year
2026: 7 · 2025: 1 · 2024: 1
FWCI
2.39
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by-nc-nd)
Funders
  • Women and Children's Health Research Institute (RGPIN-2023-05422)
  • University of Alberta
  • Canadian Institutes of Health Research (PS162449, PS162449/PS195885)
  • Natural Sciences and Engineering Research Council of Canada (rgpin-2021-02765, rgpin-2023-05422)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Keywords
endoplasmic reticulum, redox signaling, reactive oxygen species, Tom70, peroxiredoxin, mitochondrial calcium uptake, mitochondrial metabolism, neurodevelopmental disorders, glial cells, seizure-like behavior, Drosophila model
MeSH terms
Animals, Calcium, Drosophila melanogaster, Endoplasmic Reticulum, Humans, Membrane Proteins, Mitochondria, Oxidation-Reduction, Thioredoxins, Reactive Oxygen Species, Drosophila Proteins, Mitochondrial Membranes

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