[HTML][HTML] Defective mitophagy in XPA via PARP-1 hyperactivation and NAD+/SIRT1 reduction

EF Fang, M Scheibye-Knudsen, LE Brace, H Kassahun… - Cell, 2014 - cell.com
EF Fang, M Scheibye-Knudsen, LE Brace, H Kassahun, T SenGupta, H Nilsen, JR Mitchell
Cell, 2014cell.com
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 …
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.
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