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Published on: March 17, 2023
Parkin overexpression selects against a deleterious mtDNA mutation in heteroplasmic cybrid cells
Der-Fen Suen1, Derek P Narendra, Atsushi Tanaka
1Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
Mitochondrial genomes with deleterious mutations can replicate in cells along with wild-type genomes in a state of heteroplasmy, and are a cause of severe inherited syndromes, such as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS), neuropathy, ataxia, retinitis pigmentosa-maternally inherited Leigh syndrome (NARP-MILS), and Leber's hereditary optic neuropathy (LHON). The cytosolic E3 ligase, Parkin, commonly mutated in recessive familial parkinsonism, translocates to depolarized mitochondria and induces their autophagic elimination, suggesting that Parkin may signal the selective removal of defective mitochondria within the cell. We report that long-term overexpression of Parkin can eliminate mitochondria with deleterious COXI mutations in heteroplasmic cybrid cells, thereby enriching cells for wild-type mtDNA and restoring cytochrome c oxidase activity. After relieving cybrid cells of Parkin overexpression, a more favorable wild-type to mutant mitochondrial genome ratio is stably maintained. These data support the model that Parkin functions in a mitochondrial quality control pathway. Additionally, they suggest that transiently increasing levels of Parkin expression might ameliorate certain mitochondrial diseases.
Insights
Parkin protein can eliminate mitochondria with harmful mutations, restoring normal function. This suggests Parkin may be a therapeutic target for mitochondrial diseases by improving mitochondrial quality control.
Area of Science:
- Cell Biology
- Genetics
- Neuroscience
Background:
- Mitochondrial diseases arise from deleterious mutations in mitochondrial DNA (mtDNA), leading to heteroplasmy.
- Conditions like MELAS, NARP-MILS, and LHON are severe inherited syndromes caused by mtDNA mutations.
- Parkin, an E3 ligase linked to Parkinson's disease, targets depolarized mitochondria for autophagic elimination, indicating a role in mitochondrial quality control.
Purpose of the Study:
- To investigate if Parkin can eliminate mitochondria with deleterious mtDNA mutations.
- To determine if Parkin overexpression can restore cellular function in heteroplasmic cells.
- To explore the potential of Parkin in a mitochondrial quality control pathway.
Main Methods:
- Utilizing heteroplasmic cybrid cells containing both wild-type and mutated mtDNA (specifically COXI mutations).
- Long-term overexpression of the Parkin protein in these cybrid cells.
- Assessing the ratio of wild-type to mutant mtDNA and cytochrome c oxidase activity post-Parkin intervention.
Main Results:
- Long-term Parkin overexpression successfully eliminated mitochondria with deleterious COXI mutations.
- This elimination enriched cells for wild-type mtDNA, restoring cytochrome c oxidase activity.
- A favorable wild-type to mutant mtDNA ratio was stably maintained after Parkin overexpression ceased.
Conclusions:
- Parkin functions within a mitochondrial quality control pathway to remove defective mitochondria.
- Transiently increasing Parkin levels may offer a therapeutic strategy for certain inherited mitochondrial diseases.
- These findings highlight Parkin's potential in managing conditions caused by mtDNA mutations.
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