Werner syndrome (WS) is an accelerated ageing disease caused by multiple mutations in the gene encoding the Werner DNA helicase (WRN). The major clinical features of WS include wrinkles, grey hair, osteoporosis, and metabolic phenomena such as atherosclerosis, diabetes, and fatty liver, and resemble those seen in normal ageing, but occur earlier, in middle age. Defective DNA repair resulting from mutations in WRN explain the majority of the clinical features of WS, but the underlying mechanisms driving the larger metabolic dysfunction remain elusive. Recent studies in animal models of WS and in WS patient cells and blood samples suggest the involvement of impaired mitophagy, NAD⁺ depletion, and accumulation of damaged mitochondria in metabolic dysfunction. This mini-review summarizes recent progress in the understanding of the molecular mechanisms of metabolic dysfunction in WS, with the involvement of DNA damage, mitochondrial dysfunction, mitophagy reduction, stem cell impairment, and senescence. Future studies on NAD⁺ and mitophagy may shed light on potential therapeutic strategies for the WS patients.
Cytogenet Genome Res

中文翻译：

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DNA 损伤、线粒体功能障碍、线粒体自噬受损、干细胞磨损和加速衰老病 Werner 综合征衰老之间的串扰

Werner 综合征 (WS) 是一种加速衰老疾病，由编码 Werner DNA 解旋酶 (WRN) 的基因中的多个突变引起。WS的主要临床特征包括皱纹、白发、骨质疏松和动脉粥样硬化、糖尿病和脂肪肝等代谢现象，与正常衰老相似，但发生在中年更早。WRN 突变导致的有缺陷的 DNA 修复解释了 WS 的大部分临床特征，但驱动更大代谢功能障碍的潜在机制仍然难以捉摸。最近对 WS 动物模型和 WS 患者细胞和血液样本的研究表明，线粒体自噬受损、NAD ⁺代谢功能障碍中受损线粒体的消耗和积累。这篇小型综述总结了对 WS 代谢功能障碍分子机制理解的最新进展，涉及 DNA 损伤、线粒体功能障碍、线粒体自噬减少、干细胞损伤和衰老。未来对 NAD ⁺和线粒体自噬的研究可能会阐明 WS 患者的潜在治疗策略。
细胞遗传基因组研究