Genetic analysis of mitochondrial protein misfolding in Drosophila melanogaster
Open accessAbstract
Protein misfolding has a key role in several neurological disorders including Parkinson's disease. Although a clear mechanism for such proteinopathic diseases is well established when aggregated proteins accumulate in the cytosol, cell nucleus, endoplasmic reticulum and extracellular space, little is known about the role of protein aggregation in the mitochondria. Here we show that mutations in both human and fly PINK1 result in higher levels of misfolded components of respiratory complexes and increase in markers of the mitochondrial unfolded protein response. Through the development of a genetic model of mitochondrial protein misfolding employing Drosophila melanogaster, we show that the in vivo accumulation of an unfolded protein in mitochondria results in the activation of AMP-activated protein kinase-dependent autophagy and phenocopies of pink1 and parkin mutants. Parkin expression acts to clear mitochondria with enhanced levels of misfolded proteins by promoting their autophagic degradation in vivo, and refractory to Sigma P (ref(2)P), the Drosophila orthologue of mammalian p62, is a critical downstream effector of this quality control pathway. We show that in flies, a pathway involving pink1, parkin and ref(2)P has a role in the maintenance of a viable pool of cellular mitochondria by promoting organellar quality control.
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PINK1 and Parkin maintain dopaminergic neuron survival through correcting the dysfunctional mitochondrial pool.
“Subsequent studies using animal models for accelerated mitochondrial genomic error accumulation (Pickrell et al., 2015) and for mitochondrial stress through unfolded proteins (Pimenta de Castro et al., 2012) support the notion that PINK1 and Parkin maintain dopaminergic neuron survival through correcting the dysfunctional mitochondrial pool.”
From A Cell-Based High-Throughput Screening Identified Two Compounds that Enhance PINK1-Parkin Signaling (2020) · cites this paper as Pimenta de Castro et al., 2012
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References 30 · Cited by 128
- Authors
- Pimenta de Castro, I., Costa, A. C., Lam, D., Tufi, R., Fedele, V, Moisoi, N., Dinsdale, D., Deas, E., Loh, S. H. Y., & Martins, L. M.
- Affiliations
- MRC Toxicology Unit (GB)
- Universidade do Porto (PT)
- National Hospital for Neurology and Neurosurgery (GB)
- Corresponding author
- Loh, S H Y
- Martins, L M
- Venue
- Cell Death & Differentiation
- Published
- 2012-02-03
- Volume
- 19
- Issue
- 8
- Pages
- 1308-1316
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC3392634
- OpenAlex
- W2051704317
- Cited by
- 128
- References
- 30
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 5 · 2023: 5 · 2022: 9 · 2021: 8 · 2020: 9 · 2019: 3 · 2018: 6 · 2017: 11 · 2016: 11 · 2015: 11 · 2014: 14 · 2013: 14 · 2012: 9
- FWCI
- 10.01
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- www.springer.com/tdm (unspecified)
- Locations
- Cell Death and Differentiation (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Leicester Research Archive (University of Leicester) (submittedVersion, cc-by-nc-sa)
- Funders
- Wellcome Trust (089698)
- Medical Research Council (MC_G1000735)
- Fundação para a Ciência e a Tecnologia (SFRH/BD/41682/2007)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- PINK1, Parkin, p62, mitochondrial unfolded protein response, mitophagy, AMPK, mitochondrial quality control, Parkinson's disease, Drosophila melanogaster, protein aggregation
- MeSH terms
- PTEN-Induced Putative Kinase, Animals, Drosophila melanogaster, Humans, Mitochondria, Protein Serine-Threonine Kinases, Protein Folding, Protein Transport, Mitochondrial Proteins, Drosophila Proteins, Animals, Genetically Modified, Ubiquitin-Protein Ligases, HEK293 Cells
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