Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin
Abstract
Autosomal recessive juvenile parkinsonism (AR-JP) is an early-onset form of Parkinson's disease characterized by motor disturbances and dopaminergic neurodegeneration. To address its underlying molecular pathogenesis, we generated and characterized loss-of-function mutants of Drosophila PTEN-induced putative kinase 1 (PINK1), a novel AR-JP-linked gene. Here, we show that PINK1 mutants exhibit indirect flight muscle and dopaminergic neuronal degeneration accompanied by locomotive defects. Furthermore, transmission electron microscopy analysis and a rescue experiment with Drosophila Bcl-2 demonstrated that mitochondrial dysfunction accounts for the degenerative changes in all phenotypes of PINK1 mutants. Notably, we also found that PINK1 mutants share marked phenotypic similarities with parkin mutants. Transgenic expression of Parkin markedly ameliorated all PINK1 loss-of-function phenotypes, but not vice versa, suggesting that Parkin functions downstream of PINK1. Taken together, our genetic evidence clearly establishes that Parkin and PINK1 act in a common pathway in maintaining mitochondrial integrity and function in both muscles and dopaminergic neurons.
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Reduction of mitophagy caused by ablation of PINK and Parkin induces mitochondrial dysfunction and increased sensitivity to oxidative stress followed by muscle degeneration.
“Conversely, reduction of mitophagy caused by the ablation of PINK and Parkin induces mitochondrial dysfunction and increased sensitivity to oxidative stress followed by muscle degeneration [225–228].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [226]
Both excessive autophagy and deficient degradation of cytosolic components contribute to muscle atrophy.
“Both excessive autophagy [140, 186] and the deficient degradation of cytosolic components [225, 226] contribute to muscle atrophy.”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [226]
Unlike rodent PINK1 or Parkin models, Drosophila models exhibit obvious mitochondrial degeneration.
“Unlike rodent PINK1 or Parkin models, Drosophila models exhibit obvious mitochondrial degeneration (Clark et al., 2006, Park et al., 2006, Yang et al., 2006).”
From A Cell-Based High-Throughput Screening Identified Two Compounds that Enhance PINK1-Parkin Signaling (2020) · cites this paper as Park et al., 2006
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A Cell-Based High-Throughput Screening Identified Two Compounds that Enhance PINK1-Parkin Signaling
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- Authors
- Park, J., Lee, S. B., Lee, S., Kim, Y., Song, S., Kim, S., Bae, E., Kim, J., Shong, M., Kim, J.-M., & Chung, J.
- Affiliations
- Korea Advanced Institute of Science and Technology (KR)
- Corresponding author
- Chung, Jongkyeong
- ORCID
- Venue
- Nature
- Published
- 2006-05-03
- Volume
- 441
- Issue
- 7097
- Pages
- 1157-1161
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2050849483
- Cited by
- 1,705
- References
- 2
- Citations by year
- 2026: 28 · 2025: 51 · 2024: 59 · 2023: 71 · 2022: 77 · 2021: 79 · 2020: 103 · 2019: 69 · 2018: 103 · 2017: 82 · 2016: 82 · 2015: 102 · 2014: 103 · 2013: 101 · 2012: 105
- FWCI
- 63.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Korea Basic Science Institute
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- PINK1, Parkin, mitochondrial dysfunction, autosomal recessive juvenile parkinsonism, Parkinson's disease, dopaminergic neuron loss, Bcl-2, E3 ubiquitin ligase, loss-of-function mutants, gene complementation, neurodegeneration, Drosophila
- MeSH terms
- PTEN-Induced Putative Kinase, Animals, Brain, Dopamine, Drosophila melanogaster, Genetic Complementation Test, Mitochondria, Motor Activity, Mutation, Nerve Degeneration, Neurons, Phenotype, Protein Kinases, Muscle, Skeletal, Drosophila Proteins, Animals, Genetically Modified, Ubiquitin-Protein Ligases
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