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

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

SN - 0092-8674

VL - 157

SP - 882

EP - 896

JO - Cell

JF - Cell

IS - 4

ER -