Aging is associated with a decline in Atg9b-mediated autophagosome formation and appearance of enlarged mitochondria in the heart
Open accessAbstract
Advancing age is a major risk factor for developing heart disease, and the biological processes contributing to aging are currently under intense investigation. Autophagy is an important cellular quality control mechanism that is reduced in tissues with age but the molecular mechanisms underlying the age-associated defects in autophagy remain poorly characterized. Here, we have investigated how the autophagic process is altered in aged mouse hearts. We report that autophagic activity is reduced in aged hearts due to a reduction in autophagosome formation. Gene expression profile analysis to evaluate changes in autophagy regulators uncovered a reduction in Atg9b transcript and protein levels. Atg9 proteins are critical in delivering membrane to the growing autophagosome, and siRNA knockdown of Atg9b in cells confirmed a reduction in autophagosome formation. Autophagy is also the main pathway involved in eliminating dysfunctional mitochondria via a process known as mitophagy. The E3 ubiquitin ligase Parkin plays a key role in labeling mitochondria for mitophagy. We also found increased levels of Parkin-positive mitochondria in the aged hearts, an indication that they have been labeled for mitophagy. In contrast, Nrf1, a major transcriptional regulator of mitochondrial biogenesis, was significantly reduced in aged hearts. Additionally, our data showed reduced Drp1-mediated mitochondrial fission and formation of enlarged mitochondria in the aged heart. Overall, our findings suggest that cardiac aging is associated with reduced autophagosome number, decreased mitochondrial turnover, and formation of megamitochondria.
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Autophagy is inhibited in aging cells.
“Autophagy is inhibited in aging cells.”
From The mitochondrial permeability transition: Nexus of aging, disease and longevity (2021) · cites this paper as [138]
Mitophagy is inhibited in aging cells.
“Mitophagy, a specialized form of autophagy, which retards aging by removing mitochondrial fragments with activated mPTP, is also inhibited in aging cells”
From The mitochondrial permeability transition: Nexus of aging, disease and longevity (2021) · cites this paper as [138]
Autophagy capacity decreases with age.
“Autophagy capacity decreases with age.”
From The mitochondrial permeability transition: Nexus of aging, disease and longevity (2021) · cites this paper as [138]
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Autophagy in healthy aging and disease
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“Mitophagy was shown to be inhibited in aging (137,159, 202, 209 - 211) and this inhibition probably contributed to the enhancement of mPTP activity in aging.”
BackgroundCardiovascular disease and the biology of aging
Moturi, S., Ghosh-Choudhary, S. K., & Finkel, T. (2022) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2022.04.005 · Cited by 56 · see citing works
- Authors
- Liang, W., Moyzis, A. G., Lampert, M. A., Diao, R. Y., Najor, R. H., & Gustafsson, Å. B.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Gustafsson, Åsa B.
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2020-07-06
- Volume
- 19
- Issue
- 8
- Pages
- e13187-e13187
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC7431832
- OpenAlex
- W3039921807
- Cited by
- 80
- References
- 39
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 12 · 2023: 17 · 2022: 13 · 2021: 14 · 2020: 2
- FWCI
- 8.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Aging Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R21AG052280, R01HL138560, R01HL132300)
- Tobacco-Related Disease Research Program (T30FT0846)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- cardiac aging, autophagy, ATG9B, autophagosome formation, mitophagy, Parkin, NRF1, mitochondrial biogenesis, Drp1, mitochondrial fission, megamitochondria, mitochondrial turnover, heart
- MeSH terms
- Autophagosomes, Autophagy-Related Proteins, Aging, Animals, Autophagy, Heart, HeLa Cells, Humans, Male, Membrane Proteins, Mitochondria, Heart, Myocardium, Mice
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