Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan
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Aberrant protein aggregation and mitochondrial dysfunction have each been linked to aging and a number of age-onset neurodegenerative disorders, including Parkinson disease. Loss-of-function mutations in parkin , an E3 ubiquitin ligase that functions to promote the ubiquitin–proteasome system of protein degradation and also in mitochondrial quality control, have been implicated in heritable forms of Parkinson disease. The question of whether parkin can modulate aging or positively impact longevity, however, has not been addressed. Here, we show that ubiquitous or neuron-specific up-regulation of Parkin, in adult Drosophila melanogaster , increases both mean and maximum lifespan without reducing reproductive output, physical activity, or food intake. Long-lived Parkin-overexpressing flies display an increase in K48-linked polyubiquitin and reduced levels of protein aggregation during aging. Recent evidence suggests that Parkin interacts with the mitochondrial fission/fusion machinery to mediate the turnover of dysfunctional mitochondria. However, the relationships between parkin gene activity, mitochondrial dynamics, and aging have not been explored. We show that the mitochondrial fusion-promoting factor Drosophila Mitofusin, a Parkin substrate, increases in abundance during aging. Parkin overexpression results in reduced Drosophila Mitofusin levels in aging flies, with concomitant changes in mitochondrial morphology and an increase in mitochondrial activity. Together, these findings reveal roles for Parkin in modulating organismal aging and provide insight into the molecular mechanisms linking aging to neurodegeneration.
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Mitophagic processes controlled by the Parkin-Pink1 pathway may be impaired in aged muscles and are probably responsible for the ageing-related accumulation of dysfunctional mitochondria.
“Recent studies have proposed that mitophagic processes controlled by the Parkin–Pink1 pathway may be impaired in aged muscles and are probably responsible for the ageing‐related accumulation of dysfunctional mitochondria (O'Leary et al. 2013; Rana et al. 2013; Gouspillou et al. 2014b).”
From Parkin overexpression protects from ageing‐related loss of muscle mass and strength (2019) · cites this paper as Rana et al. 2013
Parkin overexpression in Drosophila skeletal muscle increases mitochondrial content and attenuates protein aggregates.
“By contrast, Parkin overexpression in Drosophila skeletal muscle was shown to increase mitochondrial content and attenuate the accumulation of protein aggregates, a marker of cellular ageing (Rana et al. 2013).”
From Parkin overexpression protects from ageing‐related loss of muscle mass and strength (2019) · cites this paper as Rana et al. 2013
Parkin overexpression in muscles of Drosophila melanogaster resulted in a significant increase in citrate synthase, complex I and complex II enzymatic activities.
“a previous study by Rana et al. (2013) showing that Parkin overexpression in muscles of Drosophila melanogaster resulted in a significant increase in citrate synthase, complex I and complex II enzymatic activities.”
From Parkin overexpression protects from ageing‐related loss of muscle mass and strength (2019) · cites this paper as Rana et al. 2013
Parkin overexpression in fly skeletal muscle and in rat hippocampal neurons stimulates mitochondrial fragmentation.
“Parkin overexpression in fly skeletal muscle and in rat hippocampal neurons has been shown to stimulate mitochondrial fragmentation (Yu et al. 2011; Rana et al. 2013).”
From Parkin overexpression protects from ageing‐related loss of muscle mass and strength (2019) · cites this paper as Rana et al. 2013
Ubiquitinated proteins accumulate in aged Drosophila muscles.
“Recent studies in Drosophila showed that ubiquitinated proteins accumulated in aged muscles[12, 13]”
From Overexpression of pink1 or parkin in indirect flight muscles promotes mitochondrial proteostasis and extends lifespan in Drosophila melanogaster (2019) · cites this paper as [13]
Parkin overexpression promotes proteostasis and tissue function of aged muscles in Drosophila and mice.
“Parkin overexpression promotes proteostasis and tissue function of aged muscles both in Drosophila and mice [13, 14]”
From Overexpression of pink1 or parkin in indirect flight muscles promotes mitochondrial proteostasis and extends lifespan in Drosophila melanogaster (2019) · cites this paper as [13]
Parkin overexpression has been shown to increase the life span in flies and reduces oxidative stress by activating mitophagy.
“Parkin overexpression has been shown to increase the life span in flies and reduces oxidative stress by activating mitophagy (50, 51).”
From Impaired mitophagy leads to cigarette smoke stress‐induced cellular senescence: implications for chronic obstructive pulmonary disease (2015) · cites this paper as [50]
Parkin overexpression in skeletal muscles of Drosophila led to higher mitochondrial citrate synthase enzymatic activity and attenuated the accumulation of protein aggregates.
“In line with these findings, Parkin overexpression in skeletal muscles of Drosophila led to higher mitochondrial citrate synthase enzymatic activity and attenuated the accumulation of protein aggregates, a marker of cellular aging [156]”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [156]
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Joy, J., Barrio, L., Santos-Tapia, C., Romão, D., Giakoumakis, N. N., Clemente-Ruiz, M., & Milán, M. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.06.009 · Cited by 63 · see citing works
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Parkin Overexpression Attenuates Sepsis-Induced Muscle Wasting
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Exercise is muscle mitochondrial medicine
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Diaminodiphenyl sulfone–induced parkin ameliorates age-dependent dopaminergic neuronal loss
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- Authors
- Rana, A., Rera, M., & Walker, D. W.
- Affiliations
- University of California, Los Angeles (US)
- Department of Integrative Biology and Physiology, and
- ORCID
- Walker, David W.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-05-06
- Volume
- 110
- Issue
- 21
- Pages
- 8638-8643
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3666724
- OpenAlex
- W2074111563
- Cited by
- 335
- References
- 53
- Citations by year
- 2026: 11 · 2025: 16 · 2024: 12 · 2023: 23 · 2022: 29 · 2021: 33 · 2020: 32 · 2019: 25 · 2018: 30 · 2017: 29 · 2016: 28 · 2015: 29 · 2014: 30 · 2013: 7
- FWCI
- 11.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- National Institute on Aging (R01AG040288, R01AG037514)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- Parkin, aging, lifespan extension, protein aggregation, proteotoxicity, mitochondrial dynamics, mitochondrial fission and fusion, mitofusins, ubiquitin-proteasome system, K48-linked polyubiquitin, mitochondrial quality control, neurodegeneration, Parkinson's disease, Drosophila melanogaster, E3 ubiquitin ligase
- MeSH terms
- Animals, Drosophila melanogaster, Gene Expression Regulation, Longevity, Membrane Proteins, Mitochondria, Neurons, Organ Specificity, Neurodegenerative Diseases, Polyubiquitin, Drosophila Proteins, Ubiquitin-Protein Ligases
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