Increased oxidative phosphorylation in response to acute and chronic DNA damage.
Increased oxidative phosphorylation in response to acute and chronic DNA damage.
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DOI：
10.1038/npjamd.2016.22
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发表时间：
2016
影响因子：
5
通讯作者：
Mitchell JR
中科院分区：
文献类型：
--
作者：
Brace LE;Vose SC;Stanya K;Gathungu RM;Marur VR;Longchamp A;Treviño-Villarreal H;Mejia P;Vargas D;Inouye K;Bronson RT;Lee CH;Neilan E;Kristal BS;Mitchell JR
DNA 损伤的积累与衰老、衰老相关疾病和早衰综合征（例如科凯恩综合征 (CS)）有着复杂的联系。内源性氧化能量代谢产生的自由基会损伤 DNA，但是急性或慢性 DNA 损伤调节细胞和/或有机体能量代谢的潜力在很大程度上仍未被探索。我们使用 DNA 修复缺陷的 Csa−/−|Xpa−/− CS 小鼠模型模拟了慢性内源性基因毒性应激。在小鼠体内和体外原代细胞中模拟外源性基因毒性应激，并用不同的基因毒素处理，产生不同范围的损伤，包括紫外线辐射、链内交联剂和电离辐射。慢性内源性和急性外源性基因毒性应激都会增加机体水平上的线粒体脂肪酸氧化（FAO），表现为耗氧量增加、呼吸交换率降低、进行性脂肪损失和离体组织中FAO增加。在多种原代细胞类型中，对不同基因毒素的代谢反应表现为细胞自主氧化磷酸化 (OXPHOS) 增加，随后稳态 NAD+ 和 ATP 水平短暂下降，并且需要 DNA 损伤传感器 PARP-1 和能量感应激酶 AMPK。我们的结论是，FAO/OXPHOS 的增加是细胞和有机体水平上对 DNA 损伤的一种普遍的、有益的、适应性的反应，说明了基因毒性应激和由 DNA 损伤的能量消耗驱动的能量代谢之间的基本联系。我们的研究指出了在放射/化疗或早衰综合征背景下减轻 DNA 损伤对原代细胞有害影响的治疗机会。
Accumulation of DNA damage is intricately linked to aging, aging-related diseases and progeroid syndromes such as Cockayne syndrome (CS). Free radicals from endogenous oxidative energy metabolism can damage DNA, however the potential of acute or chronic DNA damage to modulate cellular and/or organismal energy metabolism remains largely unexplored. We modeled chronic endogenous genotoxic stress using a DNA repair-deficient Csa−/−|Xpa−/− mouse model of CS. Exogenous genotoxic stress was modeled in mice in vivo and primary cells in vitro treated with different genotoxins giving rise to diverse spectrums of lesions, including ultraviolet radiation, intrastrand crosslinking agents and ionizing radiation. Both chronic endogenous and acute exogenous genotoxic stress increased mitochondrial fatty acid oxidation (FAO) on the organismal level, manifested by increased oxygen consumption, reduced respiratory exchange ratio, progressive adipose loss and increased FAO in tissues ex vivo. In multiple primary cell types, the metabolic response to different genotoxins manifested as a cell-autonomous increase in oxidative phosphorylation (OXPHOS) subsequent to a transient decline in steady-state NAD+ and ATP levels, and required the DNA damage sensor PARP-1 and energy-sensing kinase AMPK. We conclude that increased FAO/OXPHOS is a general, beneficial, adaptive response to DNA damage on cellular and organismal levels, illustrating a fundamental link between genotoxic stress and energy metabolism driven by the energetic cost of DNA damage. Our study points to therapeutic opportunities to mitigate detrimental effects of DNA damage on primary cells in the context of radio/chemotherapy or progeroid syndromes.