P2‐114: Extracellular mitochondrial transcription factor A (Tfam) as a potential signaling molecule that promotes inflammation and induces microglia‐mediated neurotoxicity
Bibliographic record
Abstract
Recent findings indicate that mitochondrial proteins released from injured or dying cells contain damage associated molecular patterns (DAMPs) that activate innate immune responses and promote inflammation in peripheral tissues. Given that chronic brain inflammation is linked to neuronal death in Alzheimer's disease (AD), we explored a potential role for mitochondrial DAMPs as signaling molecules that could activate microglia. Human THP-1 monocytic cells and peripheral blood mononuclear cells (PBMCs) prepared from healthy human donors were used to model microglia. An established cell culture model of neuroinflammation involving transfer of conditioned media from monocytic cells to human SH-SY5Y neuroblastoma cells was used to examine whether mitochondrial proteins promoted inflammation and caused monocyte-mediated neurotoxicity. In order to further explore specific mitochondrial proteins responsible for inducing inflammation, we made and tested purified recombinant human mitochondrial transcription factor A (Tfam), which is the mitochondrial homologue of high-mobility group box (HMGB1), a nuclear transcription factor recently implicated in neuroinflammation. Pro-inflammatory cytokine mRNA expression in THP-1 cells exposed to Tfam was also assessed by quantitative real-time PCR. Conditioned media from THP-1 cells stimulated for 48 h with isolated mitochondrial proteins (50-100 μg/ml) or Tfam (1.25-5 μg/ml) combined with interferon (IFN)-γ (150 U/ml) induced SH-SY5Y neuroblastoma cell death, which could be detected after 72 h incubation by the MTT assay (P<0.05). Tfam combined with IFN-γ also induced neurotoxic secretions from PBMCs. Tfam upregulated mRNA expression of interleukin (IL)-1β, IL-6, and IL-8 in THP-1 cells (P<0.05), an effect that was augmented (P<0.05) by costimulation with IFN-γ. Tfam was not directly cytotoxic to THP-1 or SH-SY5Y cells. Heating (95°C for 10 min) Tfam prior to stimulation of THP-1 cells significantly reduced its activity (P<0.05), while pre-treatment with polymixin B had no effect, indicating that the effects observed by using the recombinant protein were not due to endotoxin contamination. These findings indicate that mitochondrial DAMPS, in particular Tfam, could be detected by mononuclear phagocytes including microglia and have the potential to induce their neurotoxicity and pro-inflammatory cytokine secretion. Whether Tfam or other mitochondrial proteins released from damaged or dying neurons promote neuroinflammation in AD brain remains to be determined.
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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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".