Noncanonical role of astrocytic mitochondrial Cx43: suppressing IDH3α to sustain glycolytic homeostasis against depression
Bibliographic record
Abstract
Depression remains a pervasive global health challenge, compounded by limited therapeutic efficacy that is partly attributed to incompletely understood metabolic underpinnings. In this study, we reveal a noncanonical mitochondrial function of astrocytic connexin 43 (Cx43) whereby it directly inhibits isocitrate dehydrogenase 3α (IDH3α), thereby sustaining glycolytic metabolism and lactate production essential for neuronal excitability. Astrocyte-specific deletion of Cx43 in the prelimbic cortex (PrL) recapitulates hallmark depressive phenotypes, characterized by reduced lactate synthesis, diminished neuronal excitability, and depressive-like behaviors. Loss of Cx43 enhances IDH3α activity, prompting a metabolic reprogramming from aerobic glycolysis toward oxidative phosphorylation (OXPHOS) driven by glutamine-fueled anaplerosis, resulting in suppressed glucose uptake and decreased lactate output. This metabolic impairment restricts astrocytic lactate supply, depriving neurons of a critical energetic substrate. Importantly, this reprogramming occurs independently of gap junction intercellular communication, as demonstrated using a channel function-deficient dominant-negative Cx43 mutant. Restoration of mitochondrial Cx43 in astrocytes rescues neuronal excitability and ameliorates depressive-like phenotypes. Collectively, our findings identify mitochondrial Cx43 as a vital regulator of IDH3α activity, essential for astrocyte-neuron metabolic coupling, and highlight a promising target for therapeutic intervention in depression.
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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 | 0.000 | 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) | 0.000 | 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".