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Autophagy. 2014 Aug;10(8):1468-9. doi: 10.4161/auto.29321. Epub 2014 Jun 12.

Contribution of defective mitophagy to the neurodegeneration in DNA repair-deficient disorders.

Author information

1
Laboratory of Molecular Gerontology; National Institute on Aging; National Institutes of Health; Baltimore, MD USA.

Abstract

DNA repair is a prerequisite for life as we know it, and defects in DNA repair lead to accelerated aging. Xeroderma pigmentosum group A (XPA) is a classic DNA repair-deficient disorder with patients displaying sun sensitivity and cancer susceptibility. XPA patients also exhibit neurodegeneration, leading to cerebellar atrophy, neuropathy, and hearing loss, through a mechanism that has remained elusive. Using in silico, in vitro, and in vivo studies, we discovered defective mitophagy in XPA due to PARP1 hyperactivation and NAD(+) (and thus, SIRT1) depletion. This leads to mitochondrial membrane hyper-polarization, PINK1 cleavage and defective mitophagy. This study underscores the importance of mitophagy in promoting a healthy pool of mitochondria and in preventing neurodegeneration and premature aging.

KEYWORDS:

DNA repair; SIRT1; autophagy; mitophagy; xeroderma pigmentosum group A

PMID:
24991831
PMCID:
PMC4203523
DOI:
10.4161/auto.29321
[Indexed for MEDLINE]
Free PMC Article

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