Mitochondrial fragmentation is a novel feature of adherent‐invasive <i>E. coli</i> evoked pathophysiology in enteric epithelia
Bibliographic record
Abstract
Introduction Mitochondria are not distinct organelles; they exist as a dynamic network that constantly remodels via the processes of fission and fusion to meet the cells energy demands and allow recycling of damaged mitochondria. Mitochondrial dysfunction has been described in inflammatory bowel disease, where adherent‐invasive E. coli (AIEC) have been described as a pathobiont that can drive epithelial apoptosis. Little is known of microbial regulation of enterocytic mitochondrial dynamics and nothing of the potential of AIEC to perturb the critical metabolic function that mitochondria fulfill for the cell. Hypothesis AIEC induce mitochondrial fragmentation in intestinal epithelial cells in an invasion‐dependent manner that requires ROS, and drives the loss of epithelial permeability. Aim Explore the relationship between mitochondrial dynamics and epithelial function in vitro and determine if, then how, infection with AIEC affects mitochondrial dynamics and any consequence for epithelial barrier function. Methods Human colon‐derived epithelial lines were cultured with AIEC or a non‐invasive E. coli and readouts assessed: (a) visualization of mitochondria morphology and membrane potential with confocal microscopy; (b) immunoblotting of whole cell protein extracts for the mitochondrial fusion protein Optic Atrophy Factor 1 (OPA1); (c) ROS neutralized by the antioxidants; (d) treatment with spent medium from bacterial cultures; and, (e) blockade of fission using specific pharmacological inhibitors and measurement of epithelial permeability in response to AIEC. Results AIEC infection resulted in reduced mitochondrial membrane potential and ATP, and dramatic mitochondrial fragmentation accompanied by OPA1 cleavage in gut epithelia in a time‐ and dose‐dependent manner. The mitochondrial fragmentation was not reproduced by exposure to AIEC conditioned medium and was not abrogated by treatment with a general (vitamin C) or a mitochondrial‐specific (mitoTEMPO) anti‐oxidant co‐treatment. Invasion of epithelial cells by AIEC and transepithelial resistance were unaffected by co‐treatment with pharmacological inhibitor of mitochondria fission. Conclusion As a putative cause or contributor to Crohn's disease, AIEC were found to drive massive mitochondrial fragmentation in model gut epithelia independent of ROS generation or AIEC soluble factors. Neither the invasion of the E. coli nor the increase in paracellular permeability they evoke is sensitive to treatment with inhibitors of mitochondrial fission. Support or Funding Information Acknowledgements: Supported by: CIHR operating grant to DMM, U. Calgary Eyes High Doctoral Studentship to NLM.
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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 | 0.000 |
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".