Defective Mitophagy in XPA via PARP-1 Hyperactivation and NAD+/SIRT1 Reduction
Open accessAbstract
Mitochondrial dysfunction is a common feature in neurodegeneration and aging. We identify mitochondrial dysfunction in xeroderma pigmentosum group A (XPA), a nucleotide excision DNA repair disorder with severe neurodegeneration, in silico and in vivo. XPA-deficient cells show defective mitophagy with excessive cleavage of PINK1 and increased mitochondrial membrane potential. The mitochondrial abnormalities appear to be caused by decreased activation of the NAD(+)-SIRT1-PGC-1α axis triggered by hyperactivation of the DNA damage sensor PARP-1. This phenotype is rescued by PARP-1 inhibition or by supplementation with NAD(+) precursors that also rescue the lifespan defect in xpa-1 nematodes. Importantly, this pathogenesis appears common to ataxia-telangiectasia and Cockayne syndrome, two other DNA repair disorders with neurodegeneration, but absent in XPC, a DNA repair disorder without neurodegeneration. Our findings reveal a nuclear-mitochondrial crosstalk that is critical for the maintenance of mitochondrial health.
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PARP inhibition or NAD+ supplementation alleviates some premature ageing phenotypes associated with DNA repair defects by restoring mitochondrial function and mitophagy.
“Inhibition of PARP or supplementation of NAD+ was reported to alleviate some premature ageing phenotypes associated with defects in DNA repair by restoring mitochondrial function and mitophagy29.”
From The central role of DNA damage in the ageing process (2021) · cites this paper as [29]
During normal aging, lower NAD+ levels are observed in tissues of humans, mice, and C. elegans.
“During normal aging, lower NAD+ levels are observed in tissues of various organisms including humans, mice, and C. elegans.”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Fang et al., 2014
Organismal NAD+ decreases with age in wild-type worms.
“Similarly, an age-dependent reduction of organismal NAD+ in wild-type (WT) worms has been shown (Fang et al., 2014).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Fang et al., 2014
Possible causes of reduced cellular NAD+ during aging include increased consumption by PARPs and CD38 and reduced production, as evidenced by reduced eNAMPT in aged mice and humans.
“Possible explanations for reduced cellular NAD+ during aging include increased NAD+ consumption by PARPs and CD38 (Camacho-Pereira et al., 2016; Fang et al., 2014) and reduced NAD+ production, such as that evidenced by reduced eNAMPT in the aged mice and humans (Yoshida et al., 2019).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Fang et al., 2014
NAD+ depletion occurs in accelerated aging diseases with neurodegeneration, including ataxia telangiectasia, xeroderma pigmentosum group A, and Cockayne syndrome.
“Several accelerated aging diseases exhibit neurodegeneration, including ataxia telangiectasia (AT), xeroderma pigmentosum group A (XPA), and Cockayne syndrome (CS). NAD+ depletion has been shown in both C. elegans and brain tissues from mouse models of AT, XPA, and CS.”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Fang et al., 2014
In brain tissues from old normal mice and accelerated aging mice, declining NAD+ contributes to age-associated decline in mitochondrial biogenesis via impaired SIRT1-PGC-1a signaling.
“In brain tissues from old normal mice and accelerated aging mice, a decline in NAD+ levels contributes to the age-associated decline of mitochondrial biogenesis via impaired SIRT1-PGC-1a signaling (Fang et al., 2014; Mouchiroud et al., 2013; Stein and Imai, 2014).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Fang et al., 2014
NAD+ is central to mitochondrial homeostasis, including mitochondrial biogenesis, mitophagy, UPRmt, and nuclear-mitochondrial communication.
“NAD+ is central to mitochondrial homeostasis, including in mitochondrial biogenesis, mitophagy, the mitochondrial unfolded protein response (UPRmt), and nuclear-mitochondrial communication (Fang et al., 2014; Gomes et al., 2013; Mouchiroud et al., 2013).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Fang et al., 2014
NAD+ depletion acts as a phenotypic driver in several DNA damage-induced diseases, including at least Cockayne syndrome, XPA, and ataxia-telangiectasia, because restoring tissue NAD+ by inhibiting PARPs ameliorates disease pathologies.
“Moreover, NAD+ depletion is evident as a phenotypic driver in many of these DNA damage-induced diseases, including at least CS, XPA, and A-T, since restoration of tissue NAD+ through PARPs inhibition ameliorates disease pathologies (Fang et al., 2014).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Fang et al., 2014
Fang et al. observed that the XPA−/− phenotype includes neurological features similar to mitochondrial diseases and abnormal mitochondrial energy metabolism, even though cytoplasmic XPA in XPA-proficient cells was absent from the mitochondrial matrix.
“Using a bioinformatics analysis Fang et al. observed that the XPA−/− phenotype includes neurological features similar to mitochondrial diseases, and results in abnormal mitochondrial energy metabolism, even though cytoplasmic XPA in XPA-proficient cells was absent from the mitochondrial matrix 90.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [90]
Fang et al. reported increased PARP1 activity, higher protein parsylation, NAD+ depletion, and reduced mitochondrial energy generation in XPA−/− cells.
“They also reported increased poly(ADP-ribose) polymerase 1 (PARP1) activity, resulting in higher parsylation of cellular proteins resulting in NAD+ depletion, thus reducing mitochondrial energy generation.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [90]
NAD+ depletion is reported in several models of accelerated ageing that exhibit neurodegeneration, as well as in neurodegenerative diseases including Alzheimer disease, Parkinson disease and amyotrophic lateral sclerosis.
“NAD+ depletion is reported in several models of accelerated ageing which exhibit neurodegeneration33,134,135, as well as in neuro-degenerative diseases, including Alzheimer disease136, Parkinson disease137,138 and amyotrophic lateral sclerosis (ALS)139.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [134]
NAD+ replenishment using NR and/or NMN delays progeroid phenotype and extends lifespan in C. elegans models of xeroderma pigmentosum group A, ataxia telangiectasia and Cockayne syndrome, and in a worm model of Werner syndrome.
“NAD+ replenishment, using NR and/or NMN, has also been effective in delaying progeroid phenotype and extending lifespan in relevant C. elegans models of xeroderma pigmentosum group A, ataxia telangiectasia and Cockayne syndrome33,134,135 and in a worm model of Werner syndrome (a progeroid disease)196.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [134]
Accumulation of damaged or dysfunctional mitochondria due to impaired mitophagy is associated with many pathologic conditions.
“Accumulation of damaged or dysfunctional mitochondria, due to impaired mitophagy, has been associated with many pathologic conditions (22–24).”
From Impaired mitophagy leads to cigarette smoke stress‐induced cellular senescence: implications for chronic obstructive pulmonary disease (2015) · cites this paper as [24]
In these models, supplying NAD+ pharmacologically or blocking PARP1 restores SIRT1 activity and mitochondrial homeostasis.
“Pharmacological NAD+ supplementation or inhibition of PARP1 was able to re-establish SIRT1 activity and recover mitochondrial homeostasis85,86.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [85]
Animal models and patient-derived cells for xeroderma pigmentosum and Cockayne syndrome show lower SIRT1 activity and sustained PARP activation caused by unrepaired DNA damage.
“Additionally, studies conducted in animal models and cells derived from people affected by xeroderma pigmentosum and Cockayne syndrome found decreased SIRT1 activity and persistent PARP activation due to unrepaired DNA damage.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [85]
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Self-citation
- Authors
- Fang, E. F., Scheibye-Knudsen, M., Brace, L. E., Kassahun, H., SenGupta, T., Nilsen, H., Mitchell, J. R., Croteau, D. L., & Bohr, V. A.
- Affiliations
- National Institutes of Health (US)
- Harvard University (US)
- University of Oslo (NO)
- University of Copenhagen (DK)
- Corresponding author
- Bohr, Vilhelm A.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 157
- Issue
- 4
- Pages
- 882-896
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4625837
- OpenAlex
- W2040414192
- Cited by
- 711
- References
- 31
- Citations by year
- 2026: 45 · 2025: 56 · 2024: 52 · 2023: 60 · 2022: 77 · 2021: 93 · 2020: 82 · 2019: 52 · 2018: 48 · 2017: 51 · 2016: 46 · 2015: 36 · 2014: 12
- FWCI
- 36.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (ZIAAG000733, ZIAAG000722)
- National Institute of Environmental Health Sciences (T32ES016645)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- XPA, mitophagy, NAD+, SIRT1, PGC-1α, mitochondrial dysfunction, neurodegeneration, mitochondrial membrane potential, DNA damage recognition, ataxia telangiectasia, Cockayne syndrome, XPC, nuclear-mitochondrial crosstalk, lifespan, nematodes, DNA repair disorders
- MeSH terms
- Uncoupling Protein 2, PTEN-Induced Putative Kinase, Aging, Animals, Autophagy, Cell Line, Humans, Ion Channels, Poly(ADP-ribose) Polymerases, Protein Kinases, Xeroderma Pigmentosum, Caenorhabditis elegans, Apoptosis, Mitochondrial Proteins, Mice, Rats, Xeroderma Pigmentosum Group A Protein, Sirtuin 1, Mitophagy
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