The ER Thioredoxin-Related Transmembrane Protein TMX2 Controls Redox-Mediated Tethering of ER-Mitochondria Contacts (ERMCS)
Bibliographic record
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".