Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin
Abstract
Parkinson's disease is the second most common neurodegenerative disorder and is characterized by the degeneration of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction has been implicated as an important trigger for Parkinson's disease-like pathogenesis because exposure to environmental mitochondrial toxins leads to Parkinson's disease-like pathology. Recently, multiple genes mediating familial forms of Parkinson's disease have been identified, including PTEN-induced kinase 1 (PINK1; PARK6) and parkin (PARK2), which are also associated with sporadic forms of Parkinson's disease. PINK1 encodes a putative serine/threonine kinase with a mitochondrial targeting sequence. So far, no in vivo studies have been reported for pink1 in any model system. Here we show that removal of Drosophila PINK1 homologue (CG4523; hereafter called pink1) function results in male sterility, apoptotic muscle degeneration, defects in mitochondrial morphology and increased sensitivity to multiple stresses including oxidative stress. Pink1 localizes to mitochondria, and mitochondrial cristae are fragmented in pink1 mutants. Expression of human PINK1 in the Drosophila testes restores male fertility and normal mitochondrial morphology in a portion of pink1 mutants, demonstrating functional conservation between human and Drosophila Pink1. Loss of Drosophila parkin shows phenotypes similar to loss of pink1 function. Notably, overexpression of parkin rescues the male sterility and mitochondrial morphology defects of pink1 mutants, whereas double mutants removing both pink1 and parkin function show muscle phenotypes identical to those observed in either mutant alone. These observations suggest that pink1 and parkin function, at least in part, in the same pathway, with pink1 functioning upstream of parkin. The role of the pink1-parkin pathway in regulating mitochondrial function underscores the importance of mitochondrial dysfunction as a central mechanism of Parkinson's disease pathogenesis.
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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 [227]
PINK1-Parkin signaling maintains mitochondrial health.
“Early-onset Parkinson's disease-associated PINK1-Parkin signaling maintains mitochondrial health.”
From A Cell-Based High-Throughput Screening Identified Two Compounds that Enhance PINK1-Parkin Signaling (2020) · cites this paper as Clark et al., 2006
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 Clark et al., 2006
In Drosophila, knocking out either Parkin or Pink1 caused muscle degeneration that was associated with enlarged mitochondria.
“Although there are conflicting data regarding the specific effects of these proteins on mitochondrial morphology in mammalian cells, extensive studies in Drosophila revealed that knocking out either gene caused muscle degeneration that was associated with enlarged mitochondria (Clark et al., 2006; Greene et al., 2003).”
From New insights into the role of mitochondria in aging: mitochondrial dynamics and more (2010) · cites this paper as Clark et al., 2006
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- Authors
- Clark, I. E., Dodson, M. W., Jiang, C., Cao, J. H., Huh, J. R., Seol, J. H., Yoo, S. J., Hay, B. A., & Guo, M.
- Affiliations
- University of California, Los Angeles (US)
- California Institute of Technology (US)
- Seoul National University (KR)
- Kyung Hee University (KR)
- Corresponding author
- Guo, Ming
- Venue
- Nature
- Published
- 2006-05-03
- Volume
- 441
- Issue
- 7097
- Pages
- 1162-1166
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2143161560
- Cited by
- 1,788
- References
- 32
- Citations by year
- 2026: 35 · 2025: 62 · 2024: 56 · 2023: 58 · 2022: 79 · 2021: 99 · 2020: 112 · 2019: 77 · 2018: 100 · 2017: 92 · 2016: 90 · 2015: 101 · 2014: 104 · 2013: 116 · 2012: 116
- FWCI
- 63.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Alfred P. Sloan Foundation
- California Institute of Technology
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- PINK1, Parkin, Parkinson's disease, Drosophila, mitochondrial dysfunction, mitochondrial morphology, male sterility, muscle degeneration, oxidative stress sensitivity, neurodegeneration, E3 ubiquitin ligase, mitochondrial cristae, dopaminergic neurons
- MeSH terms
- PTEN-Induced Putative Kinase, Adenosine Triphosphate, Animals, Drosophila melanogaster, Epistasis, Genetic, Genetic Complementation Test, Humans, Infertility, Male, Longevity, Male, Mitochondria, Muscles, Mutation, Parkinson Disease, Phenotype, Protein Kinases, Spermatids, Apoptosis, Protein Transport, Drosophila Proteins, Ubiquitin-Protein Ligases
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