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Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology
DANIEL H. BARNETT, Till S. Zimmer, Caroline Booraem, Fernando Palaguachi, Samantha M. Meadows, Haopeng Xiao, Man Ying Wong, Wenjie Luo et al.. Nature Metabolism, 2025-11-04
Topic: Brain proteins, microglia and lab models
Neurodegenerative disorders alter mitochondrial functions, including the production of reactive oxygen species (ROS). Mitochondrial complex III (CIII) generates ROS implicated in redox signalling, but its triggers, temporal dynamics, targets and disease relevance are not clear. Here, using site-selective suppressors and genetic manipulations together with live mitochondrial ROS imaging and multiomic profiling, we show that CIII is a dominant source of ROS production in astrocytes exposed to neuropathology-related stimuli. Astrocytic CIII ROS production is dependent on nuclear factor-κB and the mitochondrial sodium-calcium exchanger (NCLX) and causes oxidation of select cysteines within immune- and metabolism-associated proteins linked to neurological disease. CIII ROS amplify metabolomic and pathology-associated transcriptional changes in astrocytes, with STAT3 activity as a major mediator, and facilitate neuronal toxicity. Therapeutic suppression of CIII ROS in mice decreases dementia-linked tauopathy and neuroimmune cascades and extends lifespan. Our findings establish CIII ROS as an important immunometabolic signal transducer and tractable therapeutic target in neurodegenerative disease.
Key findings
- Our findings establish CIII ROS as an important immunometabolic signal transducer and tractable therapeutic target in neurodegenerative disease.
Why it matters
In this study, suppressing reactive oxygen species from mitochondrial complex III in mice reduced dementia-linked tauopathy and neuroimmune changes and extended lifespan. This identifies a possible therapeutic target but the work is in animal models and does not yet show benefit in people.
Study details
- Evidence strengthLow
How this study scored 46/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Nature Metabolism) |
| Journal's citation record | 1 / 4 | Nature Metabolism: journal h-index 148 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 3 / 7 | Cited 34 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 11.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 4 / 6 | Cited 8.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 2 / 4 | Cited 34 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Adam L. Orr: h-index 28 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 7 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41188644) |
| Free to read | 2 / 2 | Free to read |
| Total | 46 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1038/s42255-025-01390-y
- PubMed: 41188644
- Original source →
- Free full text: Nature Metabolism →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
BARNETT, D. H., Zimmer, T. S., Booraem, C., Palaguachi, F., Meadows, S. M., Xiao, H., et al. (2025). Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology. Nature Metabolism. https://doi.org/10.1038/s42255-025-01390-y
Vancouver
BARNETT DH, Zimmer TS, Booraem C, Palaguachi F, Meadows SM, Xiao H, et al. Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology. Nature Metabolism. 2025. doi:10.1038/s42255-025-01390-y. PMID: 41188644.
BibTeX
@article{barnett2025-41188644,
author = {BARNETT, DANIEL H. and Zimmer, Till S. and Booraem, Caroline and Palaguachi, Fernando and Meadows, Samantha M. and Xiao, Haopeng and Wong, Man Ying and Luo, Wenjie and others},
title = {{Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology}},
journal = {Nature Metabolism},
year = {2025},
doi = {10.1038/s42255-025-01390-y},
pmid = {41188644},
url = {https://doi.org/10.1038/s42255-025-01390-y}
}
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here.