Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction

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Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. / Fang, Evandro Fei; Scheibye-Knudsen, Morten; Brace, Lear E; Kassahun, Henok; SenGupta, Tanima; Nilsen, Hilde; Mitchell, James R; Croteau, Deborah L; Bohr, Vilhelm A.

In: Cell, Vol. 157, No. 4, 08.05.2014, p. 882-96.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Fang, EF, Scheibye-Knudsen, M, Brace, LE, Kassahun, H, SenGupta, T, Nilsen, H, Mitchell, JR, Croteau, DL & Bohr, VA 2014, 'Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction', Cell, vol. 157, no. 4, pp. 882-96. https://doi.org/10.1016/j.cell.2014.03.026

APA

Fang, E. F., Scheibye-Knudsen, M., Brace, L. E., Kassahun, H., SenGupta, T., Nilsen, H., ... Bohr, V. A. (2014). Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell, 157(4), 882-96. https://doi.org/10.1016/j.cell.2014.03.026

Vancouver

Fang EF, Scheibye-Knudsen M, Brace LE, Kassahun H, SenGupta T, Nilsen H et al. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell. 2014 May 8;157(4):882-96. https://doi.org/10.1016/j.cell.2014.03.026

Author

Fang, Evandro Fei ; Scheibye-Knudsen, Morten ; Brace, Lear E ; Kassahun, Henok ; SenGupta, Tanima ; Nilsen, Hilde ; Mitchell, James R ; Croteau, Deborah L ; Bohr, Vilhelm A. / Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. In: Cell. 2014 ; Vol. 157, No. 4. pp. 882-96.

Bibtex

@article{8893d558db204b7ea737061883e6b7c8,
title = "Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction",
abstract = "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.",
keywords = "Aging, Animals, Apoptosis, Autophagy, Caenorhabditis elegans, Cell Line, Humans, Ion Channels, Mice, Mitochondrial Degradation, Mitochondrial Proteins, Poly(ADP-ribose) Polymerases, Protein Kinases, Rats, Sirtuin 1, Xeroderma Pigmentosum, Xeroderma Pigmentosum Group A Protein",
author = "Fang, {Evandro Fei} and Morten Scheibye-Knudsen and Brace, {Lear E} and Henok Kassahun and Tanima SenGupta and Hilde Nilsen and Mitchell, {James R} and Croteau, {Deborah L} and Bohr, {Vilhelm A}",
note = "Copyright {\circledC} 2014 Elsevier Inc. All rights reserved.",
year = "2014",
month = "5",
day = "8",
doi = "10.1016/j.cell.2014.03.026",
language = "English",
volume = "157",
pages = "882--96",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",

}

RIS

TY - JOUR

T1 - Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction

AU - Fang, Evandro Fei

AU - Scheibye-Knudsen, Morten

AU - Brace, Lear E

AU - Kassahun, Henok

AU - SenGupta, Tanima

AU - Nilsen, Hilde

AU - Mitchell, James R

AU - Croteau, Deborah L

AU - Bohr, Vilhelm A

N1 - Copyright © 2014 Elsevier Inc. All rights reserved.

PY - 2014/5/8

Y1 - 2014/5/8

N2 - 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.

AB - 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.

KW - Aging

KW - Animals

KW - Apoptosis

KW - Autophagy

KW - Caenorhabditis elegans

KW - Cell Line

KW - Humans

KW - Ion Channels

KW - Mice

KW - Mitochondrial Degradation

KW - Mitochondrial Proteins

KW - Poly(ADP-ribose) Polymerases

KW - Protein Kinases

KW - Rats

KW - Sirtuin 1

KW - Xeroderma Pigmentosum

KW - Xeroderma Pigmentosum Group A Protein

U2 - 10.1016/j.cell.2014.03.026

DO - 10.1016/j.cell.2014.03.026

M3 - Journal article

C2 - 24813611

VL - 157

SP - 882

EP - 896

JO - Cell

JF - Cell

SN - 0092-8674

IS - 4

ER -

ID: 119171108