Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Cell, 2014-05, Vol.157 (4), p.882-896

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Xeroderma pigmentosum group A (XPA) phenocopies mitochondrial diseases in silico•XPA deficiency leads to mitochondrial and mitophagic dysfunction across species•Dysfunctional mitophagy is caused by PARP-1 activation and attenuation of SIRT1•This mechanism is also seen in ataxia-telangiectasia and Cockayne syndrome Defective mitophagy associated with the neurodegenerative DNA repair disorder xeroderma pigmentosum is caused by activation of enzyme PARP-1 and SIRT1 attenuation via NAD+ depletion.