AMPK Preferentially Depresses Retrograde Transport of Axonal Mitochondria during Localized Nutrient Deprivation
Bibliographic record
Abstract
Mitochondrial clusters are found at regions of high-energy demand, allowing cells to meet local metabolic requirements while maintaining neuronal homeostasis. AMP-activated protein kinase (AMPK), a key energy stress sensor, responds to increases in AMP/ATP ratio by activating multiple signaling cascades to overcome the energetic deficiency. In many neurologic conditions, the distal axon experiences energetic stress independent of the soma. Here, we used microfluidic devices to physically isolate these two neuronal structures and to investigate whether localized AMPK signaling influenced axonal mitochondrial transport. Nucleofection of primary cortical neurons, derived from E16–18 mouse embryos (both sexes), with mito-GFP allowed monitoring of the transport dynamics of mitochondria within the axon, by confocal microscopy. Pharmacological activation of AMPK at the distal axon (0.1 mm 5-aminoimidazole-4-carboxamide riboside) induced a depression of the mean frequency, velocity, and distance of retrograde mitochondrial transport in the adjacent axon. Anterograde mitochondrial transport was less sensitive to local AMPK stimulus, with the imbalance of bidirectional mitochondrial transport resulting in accumulation of mitochondria at the region of energetic stress signal. Mitochondria in the axon-rich white matter of the brain rely heavily on lactate as a substrate for ATP synthesis. Interestingly, localized inhibition of lactate uptake (10 nm AR-C155858) reduced mitochondrial transport in the adjacent axon in all parameters measured, similar to that observed by 5-aminoimidazole-4-carboxamide riboside treatment. Coaddition of compound C restored all parameters measured to baseline levels, confirming the involvement of AMPK. This study highlights a role of AMPK signaling in the depression of axonal mitochondrial mobility during localized energetic stress. SIGNIFICANCE STATEMENT As the main providers of cellular energy, the dynamic transport of mitochondria within the neuron allows for clustering at regions of high-energy demand. Here we investigate whether acute changes in energetic stress signal in the spatially isolated axon would alter mitochondrial transport in this local region. Both direct and indirect activation of AMP-activated protein kinase isolated to the distal axon induced a rapid, marked depression in local mitochondrial transport. This work highlights the ability of acute localized AMP-activated protein kinase signaling to affect mitochondrial mobility within the axon, with important implications for white matter injury, axonal growth, and axonal degeneration.
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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 | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".