The Downstream Targets of Complex I Dysfunction in Bipolar Disorder
Bibliographic record
Abstract
Mitochondrial complex I dysfunction is consistently reported in bipolar disorder (BD), implicating its role in increased oxidative stress. Therefore, the overall aim of my PhD was to examine potential downstream targets of complex I dysfunction in BD. First, microarray studies examining complex I subunits in patients with BD or schizophrenia were re-evaluated to examine if complex I defect was specific to BD. Results revealed that complex I subunits that are involved in the electron transfer process are decreased only in patients with BD, suggesting that oxidative stress from complex I dysfunction may be specific to BD. Next, using post-mortem brain, I confirmed lower levels of complex I and its subunit, NDUFS7, in the frontal cortex of patients with BD, supporting the role of complex I dysfunction in the pathophysiology of BD. As an extension of a post-mortem brain study from our group demonstrating the mitochondria and the synapse as targets of oxidative stress, I first examined downstream targets of complex I dysfunction in the post-mortem brain, focusing on the mitochondria and the synapse. To demonstrate the mitochondria as a target of complex I dysfunction, I measured the activation of the NLRP3-inflammasome, which is a marker of mitochondrial oxidative stress. Results revealed that increased activation of the NLRP3-inflamamsome may be specific to BD, suggesting that mitochondria may be a target of complex I dysfunction. To examine the synapse as a target of complex I defect, I measured oxidative modifications to the dopaminergic synapse as increased dopamine signaling is known to underlie mania. Oxidative modifications to dopaminergic proteins, the dopamine transporter and tyrosine hydroxylase, were altered in the post-mortem prefrontal cortex of patients with BD, demonstrating the synapse as another potential target of complex I dysfunction in BD. Downstream targets of complex I dysfunction were further explored in cell models, allowing us to directly inhibit the electron transfer process of complex I using rotenone. The effect of lithium was also tested as it is uniquely used for the treatment of BD and therefore allows us to assess if the observed alterations may be relevant to BD pathology. Inhibiting complex I with rotenone increased protein oxidation and nitration, and caused an increase in methylation and hydroxymethylation of DNA. Moreover, lithium pre-treatment was able to decrease these alterations, suggesting that they may be downstream targets of complex I defect in BD. Together, these studies suggest that complex I dysfunction may be specific to BD, and that it may play an important role in the pathophysiology of this disease.
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 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".