Ketone-Dependent Restoration of Autophagy and Mitochondrial Quality Control Through VPS35 in a Drosophila Model of C99-Induced Neurodegeneration.

Overview

1. School of Biologycal Sciences, Adelaide University, Adelaide, SA 5000, Australia; (K.X.); (M.L.)

Abstract

Background: Early endolysosomal and autophagic defects are among the earliest cellular alterations observed in Alzheimer’s disease (AD). However, the molecular mechanisms linking amyloid precursor protein (APP) metabolism to vesicle trafficking dysfunction remain incompletely understood. The APP-derived fragment C99 has emerged as a potential upstream mediator of intracellular toxicity, but its impact on organelle homeostasis and its modulation by metabolic interventions remain unclear. Methods: To investigate these mechanisms, we expressed human C99 in Drosophila neurons and examined intracellular pathology using ultrastructural analysis, fluorescent reporters of autophagy and mitochondrial turnover, and proteomic interactome mapping. The effects of the ketone body β-hydroxybutyrate (BHB) were evaluated to assess the impact of metabolic intervention. Results: Neuronal C99 expression induced pronounced vesicular abnormalities, impaired autophagic turnover, and disrupted mitochondrial quality control. Transmission electron microscopy revealed extensive accumulation of enlarged vesicular compartments, accompanied by reduced mitochondrial turnover and accumulation of aged mitochondria. BHB treatment restored autophagic cargo clearance, improved mitochondrial turnover, and normalized vesicular ultrastructure. These protective effects required neuronal ketone transport, indicating a neuron-intrinsic metabolic mechanism. Proteomic analysis of the C99-associated interactome revealed that ketone treatment remodels networks enriched for vesicle trafficking and proteostasis pathways. Network prioritization identified the retromer component VPS35 as a candidate regulatory hub. Functional analyses demonstrated that depletion of VPS35 abolished the BHB-dependent restoration of autophagy, mitochondrial turnover, and vesicle morphology. Conclusions: Ketone treatment restores mitochondrial quality control and autophagic homeostasis through a VPS35-dependent mechanism in C99-induced neurodegeneration. These findings provide mechanistic insight into how metabolic interventions may restore intracellular homeostasis in Alzheimer’s disease.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.

The paper's code and data availability statement is in the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none (its code is available on request), so it has no map.

Data

Datasets cited

• geo:GSE5281, at NCBI GEO; found in the text, “2.7. Support Vector Machine”

Data Availability Statement

All data and code supporting the findings of this study are available upon reasonable request from the corresponding author. Due to the nature of the study, data are not publicly accessible but can be provided upon request for academic and research purposes.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 3 authors, 3 keywords, 12 MeSH terms, 45 references.

Cite

This paper

Huang, H., Xu, K., & Lardellia, M. (2026). Ketone-Dependent Restoration of Autophagy and Mitochondrial Quality Control Through VPS35 in a Drosophila Model of C99-Induced Neurodegeneration. Cells, 15(12), 1082. https://doi.org/10.3390/cells15121082

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.3389/fimmu.2026.1911726

Identification of interleukin-11 as a comorbid risk factor for prostate cancer and Alzheimer's disease using integrated bioinformatics and machine learning.

Journal: Frontiers in immunology

In common: NCBI GEO GSE5281, Alzheimer's / dementia

[2] doi:10.1038/s41598-026-55178-5

Novel approach to early prediction of alzheimer's disease progression using integrated deep regulatory genetic neural network and optimized deep belief networks.

Journal: Scientific reports

In common: NCBI GEO GSE5281, Alzheimer's / dementia

[3] doi:10.1038/s41467-026-71351-w [code]

Variants in the proteasome regulator PSMF1 cause a phenotypic spectrum from parkinsonism to perinatal lethality.

Journal: Nature communications

In common: drosophila, cellular / molecular, 1 reference

[4] doi:10.1371/journal.pbio.3003901 [code]

Peroxisomal import is circadian in glia and regulates sleep and lipid metabolism.

Journal: PLoS biology

In common: drosophila, cellular / molecular, 1 reference

[5] doi:10.1016/j.celrep.2026.117599

Immunotherapy with B28, an antibody to Aβ oligomers, potently decreases amyloid plaques, microgliosis, and memory decline in APP knock-in mice.

Journal: Cell reports

In common: Alzheimer's / dementia, cellular / molecular, 1 reference

[6] doi:10.1002/dad2.70406 [code]

Deep contrastive learning framework identifies cell-type-specific drug targets in Alzheimer's disease.

Journal: Alzheimer's & dementia (Amsterdam, Netherlands)

In common: Alzheimer's / dementia, cellular / molecular, 1 reference

[7] doi:10.1007/s42761-026-00394-5 [code]

Amygdalar Pattern Similarity to Negative and Neutral Images, Ratings of the Images, and PET-Measured Amyloid and Tau Levels in Older Adults Without Dementia.

Journal: Affective science

In common: Alzheimer's / dementia, 1 reference

[8] doi:10.1177/13872877261453512 [code]

Fluorescence spectroscopy and machine learning methods for detection of Alzheimer's disease from circulating white blood cells.

Journal: Journal of Alzheimer's disease : JAD

In common: Alzheimer's / dementia, 1 reference

[9] doi:10.1038/s41398-026-04199-9 [code]

Immune cell-specific genetic architecture of Alzheimer's disease revealed by multi-omics analysis for therapeutic target discovery and prioritization.

Journal: Translational psychiatry

In common: Alzheimer's / dementia, cellular / molecular, 1 reference

[10] doi:10.1186/s12987-026-00825-2

Acute amyloid-β exposure disrupts insulin signaling in hCMEC/D3 blood-brain barrier endothelial cells.

Journal: Fluids and barriers of the CNS

In common: Alzheimer's / dementia, cellular / molecular, 1 reference

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.

Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.