Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney
Open accessAbstract
Mitochondrial oxidative damage is a basic mechanism of aging, and multiple studies demonstrate that this process is attenuated by calorie restriction (CR). However, the molecular mechanism that underlies the beneficial effect of CR on mitochondrial dysfunction is unclear. Here, we investigated in mice the mechanisms underlying CR-mediated protection against hypoxia in aged kidney, with a special focus on the role of the NAD-dependent deacetylase sirtuin 1 (Sirt1), which is linked to CR-related longevity in model organisms, on mitochondrial autophagy. Adult-onset and long-term CR in mice promoted increased Sirt1 expression in aged kidney and attenuated hypoxia-associated mitochondrial and renal damage by enhancing BCL2/adenovirus E1B 19-kDa interacting protein 3-dependent (Bnip3-dependent) autophagy. Culture of primary renal proximal tubular cells (PTCs) in serum from CR mice promoted Sirt1-mediated forkhead box O3 (Foxo3) deacetylation. This activity was essential for expression of Bnip3 and p27Kip1 and for subsequent autophagy and cell survival of PTCs under hypoxia. Furthermore, the kidneys of aged Sirt1+/- mice were resistant to CR-mediated improvement in the accumulation of damaged mitochondria under hypoxia. These data highlight the role of the Sirt1-Foxo3 axis in cellular adaptation to hypoxia, delineate a molecular mechanism of the CR-mediated antiaging effect, and could potentially direct the design of new therapies for age- and hypoxia-related tissue damage.
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Hypoxia inhibits SIRT1 activity and prevents nuclear translocation of FOXO3, subsequent autophagy, and cell cycle arrest, leading to an increase in mitochondrial oxidative damage in kidneys of aged mice.
“hypoxia inhibits SIRT1 activity and prevents nuclear translocation of FOXO3, subsequent autophagy, and cell cycle arrest leading to an increase in mitochondrial oxidative damage in kidneys of aged mice [200].”
From Redox control of senescence and age-related disease. (2017) · cites this paper as [200]
Calorie restriction stimulates mitochondrial turnover by increasing mitochondrial biogenesis and clearance of damaged mitochondria via mitophagy.
“Moreover, calorie restriction stimulates mitochondrial turnover by boosting mitochondrial biogenesis and the clearance of damaged mitochondria via mitophagy221,222.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [221]
SIRT3 regulates electron transport chain complex II activity, Mn-SOD activity, and autophagy by deacetylation of FOXO3.
“SIRT3 has been also involved in the regulation by deacetylation of electron transport chain complex II activity (Kendrick et al., 2011), modulation of the activity of Mn-SOD (Qiu et al., 2010) or regulation of autophagy by deacetylation of FOXO3 (Kume et al., 2010).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Kume et al., 2010
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- Authors
- Kume, S., Uzu, T., Horiike, K., Chin-Kanasaki, M., Isshiki, K., Araki, S.-I., Sugimoto, T., Haneda, M., Kashiwagi, A., & Koya, D.
- Affiliations
- Shiga University of Medical Science (JP)
- Kanazawa Medical University (JP)
- Asahikawa Medical College Hospital (JP)
- Corresponding author
- Koya, Daisuke
- Venue
- Journal of Clinical Investigation
- Published
- 2010-04-01
- Volume
- 120
- Issue
- 4
- Pages
- 1043-1055
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2846062
- OpenAlex
- W2020771162
- Cited by
- 640
- References
- 65
- Citations by year
- 2026: 18 · 2025: 15 · 2024: 29 · 2023: 29 · 2022: 46 · 2021: 77 · 2020: 44 · 2019: 43 · 2018: 41 · 2017: 47 · 2016: 43 · 2015: 33 · 2014: 34 · 2013: 44 · 2012: 34
- FWCI
- 17.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Massachusetts Institute of Technology
- Harvard University
- Uehara Memorial Foundation
- Tokyo Medical and Dental University
- Japan Society for the Promotion of Science
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- caloric restriction, SIRT1, mitophagy, hypoxia, kidney aging, BNIP3, FOXO3, p27, renal proximal tubular cells, mitochondrial oxidative damage, anti-aging, NAD+-dependent deacetylase
- MeSH terms
- Forkhead Box Protein O3, Adaptation, Physiological, Aging, Animals, Autophagy, Kidney, Male, Membrane Proteins, Mice, Inbred C57BL, Mitochondria, Promoter Regions, Genetic, Cell Hypoxia, Phosphatidylinositol 3-Kinases, Mitochondrial Proteins, Caloric Restriction, Mice, Rats, Forkhead Transcription Factors, Sirtuin 1
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