Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction.
Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction.
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DOI：
10.1016/j.cell.2014.03.026
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发表时间：
2014-05-08
期刊：
影响因子：
64.5
通讯作者：
Bohr VA
中科院分区：
文献类型：
--
作者：
Fang EF;Scheibye-Knudsen M;Brace LE;Kassahun H;SenGupta T;Nilsen H;Mitchell JR;Croteau DL;Bohr VA
线粒体功能障碍是神经退行性变和衰老的共同特征。我们确定线粒体功能障碍着色性干皮病组A（XPA），核苷酸切除DNA修复障碍与严重的神经变性，在硅片和体内。XPA缺陷型细胞表现出线粒体自噬缺陷，PINK 1过度切割和线粒体膜电位增加。线粒体异常似乎是由DNA损伤传感器PARP 1的过度激活触发的NAD+-SIRT 1-PGC-1α轴的激活减少引起的。这种表型可以通过PARP 1抑制或补充NAD+前体来挽救，这也可以挽救xpa-1线虫的寿命缺陷。重要的是，这种发病机制似乎常见于共济失调-毛细血管扩张症和Cockayne综合征，这两种其他DNA修复疾病与神经变性，但不存在于XPC，一种DNA修复疾病没有神经变性。我们的研究结果揭示了一种新的核线粒体串扰，这对维持线粒体健康至关重要。
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.