Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity
Open accessAbstract
Alzheimer's disease is a common and devastating disease characterized by aggregation of the amyloid-β peptide. However, we know relatively little about the underlying molecular mechanisms or how to treat patients with Alzheimer's disease. Here we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in diseases involving amyloid-β proteotoxicity in human, mouse and Caenorhabditis elegans that involves the mitochondrial unfolded protein response and mitophagy pathways. Using a worm model of amyloid-β proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed that the induction of this mitochondrial stress response was essential for the maintenance of mitochondrial proteostasis and health. Notably, increasing mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases the fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms and in transgenic mouse models of Alzheimer's disease. Our data support the relevance of enhancing mitochondrial proteostasis to delay amyloid-β proteotoxic diseases, such as Alzheimer's disease.
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Accumulation of abnormal mitochondria without timely clearance indicates mitophagy dysfunction in Alzheimer's disease brain neurons.
“Furthermore, the accumulation of abnormal mitochondria without timely clearance indicates mitophagy dysfunction within AD brain neurons (Du et al, 2010; Sorrentino et al, 2017).”
From The mitochondrial long non-coding RNA lncMtloop regulates mitochondrial transcription and suppresses Alzheimer’s disease (2024) · cites this paper as Sorrentino et al, 2017
The Abstract reports altered mitochondrial morphology in AD, and “Evidence for a mitochondrial stress signature in AD” reports changes in mitophagy-related transcripts in human cortex. Neither passage establishes that abnormal mitochondria accumulate because clearance is delayed or that mitophagy is dysfunctional specifically in AD brain neurons; the paper instead describes induction of mitophagy-related responses. (LLM, conf=0.84)
Experimental — accuracy not yet measuredEnhanced mitochondrial proteostasis may reduce amyloid-β proteotoxicity.
“Enhanced mitochondrial proteostasis may reduce amyloid-β proteotoxicity [73]”
From Integrated analysis of ultra-deep proteomes in cortex, cerebrospinal fluid and serum reveals a mitochondrial signature in Alzheimer’s disease (2020) · cites this paper as [73]
Mitochondria from animal and post-mortem human brain tissues show age-dependent increases in functional heterogeneity, oxidative damage, reduced ETC function, disrupted membrane potential, impaired Ca2+ handling, and/or accumulation of dysfunctional mitochondria.
“Mitochondria isolated from animal and post-mortem human brain tissues show an age-dependent rise in mitochondrial functional heterogeneity, increased oxidative damage, reduced function of the ETC, disrupted membrane potential, impaired Ca2+ handling, and/or an accumulation of dysfunctional mitochondria (Lin and Beal, 2006; Mattson et al., 2008; Sorrentino et al., 2017).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Sorrentino et al., 2017
NAD+ precursors NR and NMN improve neuronal cell health, memory and cognitive function in rat and mouse models of Alzheimer disease, and show neuroprotective properties in Drosophila models of Parkinson disease and mouse models of ALS.
“the NAD+ precursors NR and NMN improve neuronal cell health, memory and cognitive function in rat and mouse models of Alzheimer disease136,161,175–180, and also showed neuroprotective properties in Drosophila melanogaster models of Parkinson disease181,182 and in mouse models of ALS139.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [179]
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Implications of NAD metabolism in pathophysiology and therapeutics for neurodegenerative diseases
Hikosaka, K., Yaku, K., Okabe, K., & Nakagawa, T. (2021) · Nutritional Neuroscience · doi:10.1080/1028415x.2019.1637504 · Cited by 62 · see citing works
A Mitochondrial Stress-Specific Form of HSF1 Protects against Age-Related Proteostasis Collapse
Williams, R., Laskovs, M., Williams, R. I., Mahadevan, A., & Labbadia, J. (2020) · Developmental Cell · doi:10.1016/j.devcel.2020.06.038 · Cited by 43 · see citing works
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Role and Potential Mechanisms of Nicotinamide Mononucleotide in Aging
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“Furthermore, the accumulation of abnormal mitochondria without timely clearance indicates mitophagy dysfunction within AD brain neurons (Du et al, 2010; Sorrentino et al, 2017).”
Molecular Perspectives of Mitochondrial Adaptations and Their Role in Cardiac Proteostasis
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- Authors
- Sorrentino, V., Romani, M., Mouchiroud, L., Beck, J. S., Zhang, H., D’Amico, D., Moullan, N., Potenza, F., Schmid, A. W., Rietsch, S., Counts, S. E., & Auwerx, J.
- Affiliations
- École Polytechnique Fédérale de Lausanne (CH)
- Michigan State University (US)
- Corresponding author
- Auwerx, Johan
- ORCID
- Venue
- Nature
- Published
- 2017-12
- Volume
- 552
- Issue
- 7684
- Pages
- 187-193
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5730497
- OpenAlex
- W2774690079
- Cited by
- 630
- References
- 54
- Citations by year
- 2026: 34 · 2025: 71 · 2024: 74 · 2023: 95 · 2022: 82 · 2021: 89 · 2020: 91 · 2019: 48 · 2018: 44 · 2017: 2
- FWCI
- 37.45
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- National University of Singapore (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- National Science Foundation (P40 OD010440, P30 AG053760)
- Velux Stiftung
- École Polytechnique Fédérale de Lausanne (665667)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (140780, 31003A)
- Associazione Italiana per la Ricerca sul Cancro
- National Institutes of Health (OD010440, AG053760, P40OD010440)
- National Institute on Aging (P30AG053760, P01AG014449, R21AG053581, R01AG043930)
- Office of Research Infrastructure Programs, National Institutes of Health (P40OD010440)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- Alzheimer's disease, amyloid-beta, mitochondrial proteostasis, mitochondrial stress response, mitochondrial unfolded protein response, mitophagy, mitochondrial translation, proteotoxic stress, protein aggregation, Caenorhabditis elegans, lifespan extension, transgenic mouse model
- MeSH terms
- Proteostasis, Alzheimer Disease, Animals, Disease Models, Animal, Homeostasis, Humans, Male, Memory, Mice, Transgenic, Mitochondria, NAD, Niacinamide, Oxidative Phosphorylation, Pyridinium Compounds, Protein Biosynthesis, Amyloid beta-Peptides, Caenorhabditis elegans, Mice, Unfolded Protein Response, Mitophagy, Protein Aggregation, Pathological
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