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Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction
- Source :
- Fang , E F , Scheibye-Knudsen , M , Brace , L E , Kassahun , H , SenGupta , T , Nilsen , H , Mitchell , J R , Croteau , D L & Bohr , V A 2014 , ' Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction ' , Cell , vol. 157 , no. 4 , pp. 882-96 .
- Publication Year :
- 2014
-
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.
Details
- Database :
- OAIster
- Journal :
- Fang , E F , Scheibye-Knudsen , M , Brace , L E , Kassahun , H , SenGupta , T , Nilsen , H , Mitchell , J R , Croteau , D L & Bohr , V A 2014 , ' Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction ' , Cell , vol. 157 , no. 4 , pp. 882-96 .
- Notes :
- English
- Publication Type :
- Electronic Resource
- Accession number :
- edsoai.ocn885449488
- Document Type :
- Electronic Resource