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

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.

Figure 1. Persistent activation of a DNA damage response by PARP1 leads to loss of NAD⁺ and attenuation of SIRT1 and PPARGC1A. This in turn leads to decreased expression of UCP2 and increased mitochondrial membrane potential. PINK1 is increasingly cleaved leading to defective mitophagy.