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SENP6 Maintains Mitochondrial Homeostasis by Regulating Mitochondrial Protein Import Through deSUMOylation of TOM40
Liubing Hu, Jianshuang Li, Haolin Guo, Lei Su, Peina Dong, Juan Huang, Yanyan Liu, Xinjie Liu et al.. Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2025-07-29
Topic: Disease mechanisms in lab and animal studies
SUMOylation, a reversible post-translational modification, regulates various mitochondrial processes, including biogenesis, dynamics, mitophagy, and the mitochondrial unfolded protein response. Although SUMOylation is shown to be triggered by mitochondrial protein import failure in yeast, its impact on mammalian mitochondrial protein import remains unclear. Here, it is demonstrated that SENP6 knockdown-induced SUMOylation causes loss of mitochondrial proteostasis, which impairs mitochondrial morphology and function. Mechanistically, SENP6 knockdown dampens TOM complex assembly by SUMOylating TOM40, thereby hindering the mitochondrial protein import process, including TOM40 precursor, and ultimately disrupts mitochondrial homeostasis. Additionally, it is observed that CCCP treatment resulted in a decrease of SENP6 within mitochondria fraction, accompanied by increased TOM40 SUMOylation in the brains of 3×Tg-Alzheimer's disease (AD) mice or Aβ1-42 peptide-stimulated cells. Collectively, the results suggest that Aβ1-42 accumulation may enhance TOM40 SUMOylation by suppressing SENP6, thereby impairing mitochondrial homeostasis through protein import failure and potentially contributing to the pathological process of AD. This study elucidates the role of TOM40 SUMOylation/deSUMOylation in regulating the mitochondrial import process during mitochondrial stress.
Key findings
- Here, it is demonstrated that SENP6 knockdown-induced SUMOylation causes loss of mitochondrial proteostasis, which impairs mitochondrial morphology and function.
- Collectively, the results suggest that Aβ1-42 accumulation may enhance TOM40 SUMOylation by suppressing SENP6, thereby impairing mitochondrial homeostasis through protein import failure and potentially contributing to the pathological process of AD.
Study details
- Evidence strengthLow
How this study scored 43/100
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. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record, multi-centre collaboration and free to read, so those were left out: it earned 24 of the 56 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Advanced science (Weinheim, Baden-Wurttemberg, Germany)) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40729740) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 24 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 24 of the 56 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Hu, L., Li, J., Guo, H., Su, L., Dong, P., Huang, J., et al. (2025). SENP6 Maintains Mitochondrial Homeostasis by Regulating Mitochondrial Protein Import Through deSUMOylation of TOM40. Advanced science (Weinheim, Baden-Wurttemberg, Germany). https://doi.org/10.1002/advs.202503408
Vancouver
Hu L, Li J, Guo H, Su L, Dong P, Huang J, et al. SENP6 Maintains Mitochondrial Homeostasis by Regulating Mitochondrial Protein Import Through deSUMOylation of TOM40. Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2025. doi:10.1002/advs.202503408. PMID: 40729740.
BibTeX
@article{hu2025-40729740,
author = {Hu, Liubing and Li, Jianshuang and Guo, Haolin and Su, Lei and Dong, Peina and Huang, Juan and Liu, Yanyan and Liu, Xinjie and others},
title = {{SENP6 Maintains Mitochondrial Homeostasis by Regulating Mitochondrial Protein Import Through deSUMOylation of TOM40}},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
year = {2025},
doi = {10.1002/advs.202503408},
pmid = {40729740},
url = {https://doi.org/10.1002/advs.202503408}
}
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