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

Evandro Fei Fang; Morten Scheibye-Knudsen; Lear E Brace; Henok Kassahun; Tanima SenGupta; Hilde Nilsen; James R Mitchell; Deborah L Croteau; Vilhelm A Bohr

doi:10.1016/j.cell.2014.03.026

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

Evandro Fei Fang, Morten Scheibye-Knudsen, Lear E Brace, Henok Kassahun, Tanima SenGupta, Hilde Nilsen, James R Mitchell, Deborah L Croteau, Vilhelm A Bohr

313 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Cell
Vol/bind	157
Udgave nummer	4
Sider (fra-til)	882-96
Antal sider	15
ISSN	0092-8674
DOI	https://doi.org/10.1016/j.cell.2014.03.026
Status	Udgivet - 8 maj 2014

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10.1016/j.cell.2014.03.026

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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}",

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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

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

SN - 0092-8674

VL - 157

SP - 882

EP - 896

JO - Cell

JF - Cell

IS - 4

ER -

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

Abstract

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