Hyperglycemia-induced mitochondrial abnormalities in autonomic neurons via the RAGE axis
Bibliographic record
Abstract
Diabetic peripheral neuropathy is characterized by mitochondrial dysfunction, including suboptimal respiration, impaired calcium homeostasis, and accumulation of reactive oxygen species (ROS). Hyperglycemia drives excessive electron donation to the mitochondria, resulting in damaging ROS levels. In peripheral neurons, hyperglycemia also leads to the formation of advanced glycation end-products (AGEs), which, through their membrane receptor (RAGE), trigger autonomic malfunction in diabetes. However, it remains unclear whether RAGE is required to induce mitochondrial abnormalities under hyperglycemia. Thus, we first investigated mitochondrial morphology in autonomic ganglia (superior cervical ganglion, SCG) from streptozotocin (STZ)-induced diabetic mice and found an enhanced proportion of swollen mitochondria with disrupted cristae in wild-type (WT) diabetic mice, but not in RAGE knock-out (KO) diabetic mice. Next, we exposed cultured SCG neurons to high glucose and found fragmentation and an imbalanced traffic represented by an increased proportion of only anterograde moving mitochondria in neurons from WT, but such imbalance was not observed in neurons from RAGE KO mice. Treating WT neurons with the non-membrane permeable RAGE selective inhibitor FPS-ZM1, did not prevent fragmentation, although a non-significant restoring trend was observed. Furthermore, ATP production was unaffected by exposure to high glucose in neurons for WT, and remained unchanged by incubation in FPS-ZM1. Interestingly, neurons from RAGE KO mice had significantly less ATP produced in all conditions than those from WT mice. Lastly, we found RAGE protein in enriched mitochondrial fractions from nerve growth factor (NGF)-transformed PC12 (PC12 NGF ) cells, as well as the colocalization of RAGE with a mitochondrial marker in cultured SCG neurons. Therefore, our data support that RAGE mediates mitochondrial damage in autonomic neurons under hyperglycemic conditions.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| 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) | 0.000 | 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 teacher head, 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".