Loss of the drosophila m-aaa mitochondrial protease paraplegin results in mitochondrial dysfunction, shortened lifespan, and neuronal and muscular degeneration
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Abstract The progressive accumulation of dysfunctional mitochondria is implicated in aging and in common diseases of the elderly. To oppose this occurrence, organisms employ a variety of strategies, including the selective degradation of oxidatively damaged and misfolded mitochondrial proteins. Genetic studies in yeast indicate that the ATPase Associated with diverse cellular Activities (AAA+) family of mitochondrial proteases account for a substantial fraction of this protein degradation, but their metazoan counterparts have been little studied, despite the fact that mutations in the genes encoding these proteases cause a variety of human diseases. To begin to explore the biological roles of the metazoan mitochondrial AAA+ protease family, we have created a CRISPR/Cas9 allele of the Drosophila homolog of SPG7, which encodes an inner membrane-localized AAA+ protease known as paraplegin. Drosophila SPG7 mutants exhibited shortened lifespan, progressive locomotor defects, sensitivity to chemical and environmental stress, and muscular and neuronal degeneration. Ultrastructural examination of photoreceptor neurons indicated that the neurodegenerative phenotype of SPG7 mutants initiates at the synaptic terminal. A variety of mitochondrial defects accompanied the degenerative phenotypes of SPG7 mutants, including altered axonal transport of mitochondria, accumulation of electron-dense material in the matrix of flight muscle mitochondria, reduced activities of respiratory chain complexes I and II, and severely swollen and dysmorphic mitochondria in the synaptic terminals of photoreceptors. Drosophila SPG7 mutants recapitulate key features of human diseases caused by mutations in SPG7, and thus provide a foundation for the identification of Drosophila paraplegin substrates and strategies that could be used to ameliorate the symptoms of these diseases.
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Mutation of Drosophila m-AAA mitochondrial protease leads to impaired mitochondria function, shortened lifespan, and neuronal and muscular degeneration.
“Mutation of Drosophila m-AAA mitochondrial protease leaded to impaired mitochondria function, shortened lifespan, and neuronal and muscular degeneration (58).”
From From mitochondria to sarcopenia: role of 17β-estradiol and testosterone (2023) · cites this paper as [58]
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- Authors
- Pareek, G., Thomas, R. E., & Pallanck, L. J.
- Affiliations
- University of Washington (US)
- Corresponding author
- Pallanck, Leo J.
- Venue
- Cell Death & Disease
- Published
- 2018-02-21
- Volume
- 9
- Issue
- 3
- Pages
- 304-304
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC5833341
- OpenAlex
- W2793832427
- Cited by
- 42
- References
- 61
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 2 · 2023: 8 · 2022: 7 · 2021: 1 · 2020: 6 · 2019: 5 · 2018: 4
- FWCI
- 1.42
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- University of Washington
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R21NS094901)
- Topics
- 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
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- paraplegin, SPG7, AAA+ protease, mitochondrial proteolysis, mitochondrial dysfunction, Drosophila, lifespan, neurodegeneration, photoreceptors, respiratory chain complexes, mitochondrial ultrastructure, locomotion defects, muscle degeneration, aging, CRISPR/Cas9 mutants
- MeSH terms
- ATPases Associated with Diverse Cellular Activities, Animals, Axons, Behavior, Animal, Drosophila melanogaster, Electron Transport, Larva, Longevity, Metalloendopeptidases, Mitochondria, Muscles, Mutation, Nerve Degeneration, Synapses, Sequence Homology, Amino Acid, Drosophila Proteins
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