Mitochondrial impairment triggers cytosolic oxidative stress and cell death following proteasome inhibition
Open accessAbstract
Dysfunctions of the mitochondria and the ubiquitin-proteasome system, as well as generation of reactive oxygen species (ROS), are linked to many aging-related neurodegenerative disorders. However, the order of these events remains unclear. Here, we show that the initial impairment occurs in mitochondria under proteasome inhibition. Fluorescent redox probe measurements revealed that proteasome inhibition led to mitochondrial oxidation followed by cytosolic oxidation, which could be prevented by a mitochondrial-targeted antioxidant or antioxidative enzyme. These observations demonstrated that proteasome dysfunction causes damage to mitochondria, leading them to increase their ROS production and resulting in cytosolic oxidation. Moreover, several antioxidants found in foods prevented intracellular oxidation and improved cell survival by maintaining mitochondrial membrane potential and reducing mitochondrial ROS generation. However, these antioxidant treatments did not decrease the accumulation of protein aggregates caused by inhibition of the proteasome. These results suggested that antioxidative protection of mitochondria maintains cellular integrity, providing novel insights into the mechanisms of cell death caused by proteasome dysfunction.
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Reduced mitophagy via Pink1/Parkin-regulated ubiquitination in aged neurons contributes to greater ROS accumulation.
“Reduced mitophagy associated Pink1- and Parkin-regulated ubiquitination of the outer mitochondrial membrane of damaged mitochondria in aged neurons (79, 99, 140) contribute to a greater accumulation of ROS (81).”
From Mitochondria initiate and regulate sarcopenia (2017) · cites this paper as [81]
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- Authors
- Maharjan, S., Oku, M., Tsuda, M., Hoseki, J., & Sakai, Y.
- Affiliations
- Kyoto University (JP)
- Corresponding author
- Hoseki, Jun
- Sakai, Yasuyoshi
- Venue
- Scientific Reports
- Published
- 2014-07-31
- Volume
- 4
- Issue
- 1
- Pages
- 5896-5896
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4116626
- OpenAlex
- W2061110648
- Cited by
- 212
- References
- 50
- Citations by year
- 2026: 7 · 2025: 20 · 2024: 18 · 2023: 11 · 2022: 16 · 2021: 27 · 2020: 23 · 2019: 18 · 2018: 18 · 2017: 19 · 2016: 15 · 2015: 17 · 2014: 3
- FWCI
- 7.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Scientific Reports (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion, cc-by-nc-sa)
- Funders
- Takeda Science Foundation
- Uehara Memorial Foundation
- Ministry of Education, Culture, Sports, Science and Technology
- Medical Research Council
- Japan Society for the Promotion of Science (23651235, 26292052, 26440050, 24780100)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- proteasome inhibition, mitochondrial dysfunction, reactive oxygen species, cell death, ubiquitin-proteasome system, mitochondrial membrane potential, mitochondria-targeted antioxidants, dietary antioxidants, protein aggregation, neurodegenerative diseases, aging
- MeSH terms
- Bortezomib, Resveratrol, Animals, Antioxidants, Boronic Acids, Cricetulus, Cricetinae, Mitochondria, Pyrazines, Stilbenes, CHO Cells, Apoptosis, Reactive Oxygen Species, Oxidative Stress, Neurodegenerative Diseases, Proteasome Endopeptidase Complex, Membrane Potential, Mitochondrial, Ubiquitination, Proteolysis, Proteasome Inhibitors
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