Contribution of defective mitophagy to the neurodegeneration in DNA repair-deficient disorders
Open accessAbstract
DNA repair is a prerequisite for life as we know it, and defects in DNA repair lead to accelerated aging. Xeroderma pigmentosum group A (XPA) is a classic DNA repair-deficient disorder with patients displaying sun sensitivity and cancer susceptibility. XPA patients also exhibit neurodegeneration, leading to cerebellar atrophy, neuropathy, and hearing loss, through a mechanism that has remained elusive. Using in silico, in vitro, and in vivo studies, we discovered defective mitophagy in XPA due to PARP1 hyperactivation and NAD(+) (and thus, SIRT1) depletion. This leads to mitochondrial membrane hyper-polarization, PINK1 cleavage and defective mitophagy. This study underscores the importance of mitophagy in promoting a healthy pool of mitochondria and in preventing neurodegeneration and premature aging.
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Premature ageing disorders caused by defective DNA repair-ataxia-telangiectasia, Cockayne syndrome group A, and xeroderma pigmentosum group A-are associated with mitochondrial changes that suggest responses to anterograde signals.
“Supporting this hypothesis, DNA repair-deficient premature ageing diseases, such as ataxia–telangiectasia (ATM), Cockayne syndrome group A and xeroderma pigmentosum group A, have been linked to changes in mitochondrial physiology, which are indicative of physiological responses to anterograde stimuli77.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [77]
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- Authors
- Scheibye-Knudsen, M., Fang, E. F., Croteau, D. L., & Bohr, V. A.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Bohr, Vilhelm A
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2014-06-12
- Volume
- 10
- Issue
- 8
- Pages
- 1468-1469
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- PMC
- PMC4203523
- OpenAlex
- W1995386040
- Cited by
- 50
- References
- 0
- Citations by year
- 2025: 2 · 2024: 9 · 2023: 3 · 2022: 3 · 2021: 8 · 2020: 4 · 2019: 1 · 2017: 5 · 2016: 6 · 2015: 7 · 2014: 2
- FWCI
- 5.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Autophagy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- mitophagy, neurodegeneration, XPA, DNA repair deficiency, NAD+ depletion, SIRT1, mitochondrial membrane hyperpolarization, premature aging, cerebellar atrophy, neuropathy, hearing loss
- MeSH terms
- Uncoupling Protein 1, Animals, DNA Damage, DNA Repair, Humans, Ion Channels, Models, Biological, Nerve Degeneration, Transcription Factors, Mitochondrial Proteins, Membrane Potential, Mitochondrial, Mitophagy
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