Defective Mitophagy in XPA via PARP1 Hyperactivation and NAD+/SIRT1 Reduction

By Evandro Fei Fang, M. Scheibye-Knudsen, L. Brace, H. Kassahun, T. Sengupta, H. Nilsen, James R. Mitchell, D. Croteau, V. Bohr. Cell, 2014

665 citations recorded by the source corpus.

SUMMARY 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 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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c7143c6e8521ee576fa45aec395d6438f8040154

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. L. Galluzzi
2. Guido Kroemer
3. R. Youle
4. Bor Luen Tang

In Molecular Biology

1. Guido Kroemer
2. L. Galluzzi
3. R. Youle
4. Frank Madeo
5. C. López‐Otín
6. Jun Yoshino
7. Toren Finkel
8. S. Imai

Citations in the corpus

• NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential (2020, background): “The accumulated DNA oxidative damage in AD hyper-activates the DNA damage sensor PARP-1, thereby reducing the concentration of cellular NAD and suppressing the function of NAD-SIRT1-PGC-1α axis, which in turn causes abnormal mitochondria.(511) Replenishing cellular NAD can promote DNA repair in neur”
• Metabolic Control of Longevity. (2016, background): “PARP1 hyperactivation leads to NAD+ depletion, hence inhibiting the NAD+-dependent deacetylase sirtuin 1 (SIRT1) (Fang et al., 2014).”
• NAD+ intermediates: The biology and therapeutic potential of NMN and NR (2017, positive): “While NR is unable to correct the primary DNA repair deficiencies, it dramatically improves phenotypes in mouse models of each of these conditions, most remarkably more than tripling survival time in ataxic mice (Fang et al., 2014, 2016; Scheibye-Knudsen et al., 2014).”
• Sirt1 and the Mitochondria (2016, background): “Mitochondrial dysfunction in Xeroderma Pigmentosum group A (XPA), a nucleotide excision DNA repair disorder, is characterized by defective mitophagy (Fang et al., 2014).”
• Cellular mitophagy: Mechanism, roles in diseases and small molecule pharmacological regulation (2023, background): “Silent information regulator T1 or Sirtuin 1 (SIRT1) is a deacetylase that regulates a variety of activities by controlling biological processes such as gene expression, DNA repair, metabolism, and mitochondrial function.”
• Mitophagy and Alzheimer’s disease: cellular and molecular mechanisms (2017, background): “Moreover, autophagic flux was apparently impeded by reduced substrate clearance (accumulation of LC3-II and p62 in autolysosomes).”
• The Mitochondrial Basis of Aging (2016, background): “Inhibition of SIRT1 decreases activation of PGC-1a, leading to defective PINK1- and Parkin-mediated mitophagy (Fang et al., 2014).”