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Defective Mitophagy in XPA via PARP-1 Hyperactivation and NAD+/SIRT1 Reduction

2014; Cell Press; Volume: 157; Issue: 4 Linguagem: Inglês

10.1016/j.cell.2014.03.026

1097-4172

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

PARP inhibition in cancer therapy

Summary 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.