Defective Mitophagy in XPA Via PARP-1 Hyperactivation and NAD(+)/SIRT1 Reduction

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2014 May 13

PMID 24813611

Citations 340

Authors

Evandro Fei Fang

Morten Scheibye-Knudsen

Lear E Brace

Henok Kassahun

Tanima SenGupta

Hilde Nilsen

James R Mitchell

Deborah L Croteau

Vilhelm A Bohr

Affiliations

Soon will be listed here.

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.

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