SIFD-associated TRNT1 deficiency unveils importance of TSPO during macrophage antibacterial and antiviral responses
Bibliographic record
Abstract
Introduction: Mitochondria support cellular biosynthetic and bioenergetic demands and mediate cell signaling. Their dysfunction is implicated in a wide range of diseases, including congenital disorders. One such disorder, sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD), is caused by mutations in the tRNA-nucleotidyltransferase enzyme TRNT1. While SIFD is known to affect immune function, the role of macrophages-key mediators between innate and adaptive immunity-remains underexplored. Methods: To investigate the impact of TRNT1 deficiency on macrophage function, we employed siRNA-mediated knockdown of TRNT1 in murine RAW264.7 macrophages. Cells were stimulated with lipopolysaccharide (LPS) and Polyinosinic:polycytidylic acid (Poly (I:C)) to mimic bacterial and viral infections, respectively. Cytokine production was measured, and mitochondrial reprogramming was assessed. Bioinformatic analysis was conducted to identify TRNT1-dependent transcripts, focusing on mitochondrial-associated proteins. Functional rescue experiments were performed using TSPO ligands and TSPO overexpression. Results: TRNT1 knockdown impaired inflammatory cytokine production in response to both LPS and Poly (I:C). This correlated with diminished mitochondrial reprogramming, suggesting a mechanistic link between TRNT1 activity and macrophage effector function. Transcriptomic analysis identified the mitochondrial translocator protein (TSPO) as a TRNT1-dependent gene. TSPO expression was differentially regulated following stimulation in TRNT1-deficient cells. While TSPO ligand activation failed to restore cytokine production, TSPO overexpression prior to TRNT1 knockdown selectively rescued the inflammatory response to Poly (I:C), but not LPS. This rescue was associated with enhanced recruitment of VDAC to the mitochondrial permeability transition pore via TSPO. Discussion: Our findings reveal that TRNT1 is critical for pathogen-specific mitochondrial reprogramming in macrophages, influencing their inflammatory capacity. The differential restoration of cytokine responses via TSPO overexpression underscores the complexity of mitochondrial signaling in immune regulation. These insights suggest that targeting mitochondrial pathways may offer a novel therapeutic strategy for managing immunodeficiency in SIFD.
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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) | 0.000 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".