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

• Published in: Cell 2014-05, Vol.157 (4), p.882-896
• Main Authors: Fang, Evandro Fei, Scheibye-Knudsen, Morten, Brace, Lear E., Kassahun, Henok, SenGupta, Tanima, Nilsen, Hilde, Mitchell, James R., Croteau, Deborah L., Bohr, Vilhelm A.
• Format: Article
• Language: English
• Subjects: Aging; Animals; Apoptosis; Autophagy; Caenorhabditis elegans; Cell Line; Humans; Ion Channels - metabolism; Mice; Mitochondrial Degradation; Mitochondrial Proteins - metabolism; Poly(ADP-ribose) Polymerases - metabolism; Protein Kinases - metabolism; Rats; Sirtuin 1 - metabolism; Uncoupling Protein 2; Xeroderma Pigmentosum - metabolism; Xeroderma Pigmentosum - physiopathology; Xeroderma Pigmentosum Group A Protein - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2014.03.026

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.