github link
Accession IconGSE55485

Defective Mitophagy in XPA via PARP1 activation and NAD+/SIRT1-depletion: Implications for neurodegeneration (mouse)

Organism Icon Mus musculus
Sample Icon 12 Downloadable Samples
Technology Badge IconIllumina MouseRef-8 v2.0 expression beadchip

Submitter Supplied Information

Description
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-1 axis triggered by hyperactivation of the DNA damage sensor PARP1. This phenotype is rescued by PARP1 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 novel nuclear-mitochondrial cross-talk that is critical for the maintenance of mitochondrial health.
PubMed ID
Total Samples
12
Submitter’s Institution

Samples

Show of 0 Total Samples
Filter
Add/Remove
Accession Code
Title
Sex
Treatment
Processing Information
Additional Metadata
No rows found
Loading...