Inhibition of apoptotic Bax translocation to the mitochondria is a central function of parkin
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Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder, affecting 1–3% of the population over 65. Mutations in the ubiquitin E3 ligase parkin are the most common cause of autosomal recessive PD. The parkin protein possesses potent cell-protective properties and has been mechanistically linked to both the regulation of apoptosis and the turnover of damaged mitochondria. Here, we explored these two functions of parkin and the relative scale of these processes in various cell types. While biochemical analyses and subcellular fractionation were sufficient to observe robust parkin-dependent mitophagy in immortalized cells, higher resolution techniques appear to be required for primary culture systems. These approaches, however, did affirm a critical role for parkin in the regulation of apoptosis in primary cultured neurons and all other cells studied. Our prior work demonstrated that parkin-dependent ubiquitination of endogenous Bax inhibits its mitochondrial translocation and can account for the anti-apoptotic effects of parkin. Having found a central role for parkin in the regulation of apoptosis, we further investigated the parkin-Bax interaction. We observed that the BH3 domain of Bax is critical for its recognition by parkin, and identified two lysines that are crucial for parkin-dependent regulation of Bax translocation. Last, a disease-linked mutation in parkin failed to influence Bax translocation to mitochondria after apoptotic stress. Taken together, our data suggest that regulation of apoptosis by the inhibition of Bax translocation is a prevalent physiological function of parkin regardless of the kind of cell stress, preventing overt cell death and supporting cell viability during mitochondrial injury and repair.
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Parkin can exert anti-apoptotic effects.
“our findings add to the available literature showing that Parkin can exert anti‐apoptotic effects (Charan et al. 2014).”
From Parkin overexpression protects from ageing‐related loss of muscle mass and strength (2019) · cites this paper as Charan et al. 2014
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- Authors
- Charan, R. A., Johnson, B. N., Zaganelli, S., Nardozzi, J. D., & LaVoie, M. J.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- LaVoie, M J
- Venue
- Cell Death & Disease
- Published
- 2014-07-03
- Volume
- 5
- Issue
- 7
- Pages
- e1313-e1313
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC4123072
- OpenAlex
- W1965110900
- Cited by
- 67
- References
- 64
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 6 · 2023: 3 · 2022: 4 · 2021: 5 · 2020: 3 · 2019: 6 · 2018: 6 · 2017: 6 · 2016: 13 · 2015: 8 · 2014: 2
- FWCI
- 6.30
- 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)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (AG000222)
- National Institute on Aging (AG000222, T32AG000222)
- National Institute of Neurological Disorders and Stroke (R01NS065013, NS065013)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- Parkin, Bax, mitochondrial translocation, apoptosis, Parkinson's disease, mitophagy, ubiquitination, BH3 domain, lysine residues, parkin mutations, primary neurons, mitochondrial injury
- MeSH terms
- Cells, Cultured, Humans, Mitochondria, Neurons, Parkinson Disease, Protein Binding, Down-Regulation, Apoptosis, Amino Acid Motifs, Protein Transport, Ubiquitin-Protein Ligases, bcl-2-Associated X Protein
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