Activity of NADH‐ and FADH2‐linked mitochondrial respiration are significantly decreased in two mice models of Parkinson’s disease
Bibliographic record
Abstract
Parkinson’s disease (PD) is a complex neurodegenerative disorder, which etiology is still largely unknown. Overwhelming evidence indicates that mitochondrial dysfunction is a central factor in PD pathophysiology. Here we tested the hypothesis that the activity of complex I and II (NADH‐and FADH 2 ‐linked mitochondrial respiration, respectively) in the substantia nigra are significantly decreased in PD. To test this hypothesis, we used two different mice models of PD: Mice that received a single unilateral intrastriatal injection of 1) 6‐OHDA (9μg ‐ a selective catecholaminergic neurotoxin), or 2) A53T‐α‐synuclein (5.62E12 GC/ml – a molecule that attenuates synaptic vesicle recycling and neurotransmitter release). Control groups were injected with vehicle (fluorescent protein). Mitochondrial oxygen consumption was evaluated by using our oxygraph‐2K system (O2k‐OROBOROS), in 2 mg weight of tissue permeabilized with saponin. Measurements were performed one week after treatment with 6‐OHDA, and five weeks after treatment with A53T‐α‐synuclein. Our preliminary results show that, compared to control animals, substrates of complex I (Pyruvate/Glutamate/Malate), in the presence of ADP (state 3 complex I), induced a reduced oxygen consumption in mice treated with 6‐OHDA,(50.65 ± 2 vs 78 ±3 pmol O2/s/mg tissue, p<0.001). Inline, compared to control animals, oxygen consumption in state 3 complex I, was significantly reduced in mice treated with α‐synuclein (31.05 ± 5 vs 43.56 ± 2 pmol O2/s/mg tissue, p<0.05). Moreover, oxygen consumption in the presence of substrates of the mitochondrial complex II (succinate – state 3‐complex II), was also significantly reduced after treatment with α‐synuclein (30.8 ± 4.5 vs 46.5 ± 5 pmol O2/s/mg tissue, p<0.05). No differences of oxygen consumption were found in the presence of PMG, but the absence of ADP (state 4 – mitochondrial membrane leak) with none of the treatments. We concluded that 6‐OHDA and α‐synuclein, two reliable models of PD, induce mitochondrial dysfunction by decreasing the activity of mitochondrial complexes I and II. Our results contribute to a better understanding of the mitochondrial dysfunction induced by PD, and open the avenue for alternative treatments aiming to avoid the degeneration of dopaminergic neurons in the substantia nigra. Support or Funding Information Jorge Soliz is supported by the “Fonds de recherche du Quebec‐Santé” (FRQ‐S; FQ121919)
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| 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".