Mitochondrial dysfunction has long been implicated to have a causative role in organismal aging. A mitochondrial molecule, nucleotide-binding domain and leucine-rich-repeat-containing protein X1 (NLRX1), represents the only NLR family member that targets this cellular location, implying that NLRX1 probably establishes a fundamental link between mitochondrial functions and cellular physiology. However, the significance of NLRX1 function in cellular senescence, a key conceptual constituent in aging biology, is yet to be defined. Here, we demonstrate that molecular hallmarks involved in aging biology including NAD⁺ decline, and activation of mTOR, p53, and p16^INK4A are significantly enhanced in NLRX1 deficiency in vitro. Mechanistic studies of replicative cellular senescence in the presence or absence of NLRX1 in vitro reveal that NLRX1-deficient fibroblasts fail to maintain optimal NAD⁺/NADH ratio, which instigates the decline of SIRT1 and the activation of mTOR, p16^INK4A, and p53, leading to the increase in senescence-associated beta-galactosidase (SA-β-gal)-positive cells. Importantly, the enhanced cellular senescence response in NLRX1 deficiency is significantly attenuated by pharmacological inhibition of mTOR signaling in vitro. Finally, our in vivo murine studies reveal that NLRX1 decreases with age in murine lungs and NLRX1 deficiency in vivo accelerates pulmonary functional and structural changes that recapitulate the findings observed in human aging lungs. In conclusion, the current study provides evidence for NLRX1 as a crucial regulator of cellular senescence and in vivo lung aging.

中文翻译：

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核苷酸结合域和富含亮氨酸重复的蛋白质 X1 缺乏诱导烟酰胺腺嘌呤二核苷酸下降、雷帕霉素激活的机制靶点和细胞衰老并加速老化的肺样变化

长期以来，线粒体功能障碍一直被认为在机体衰老中具有致病作用。线粒体分子、核苷酸结合结构域和富含亮氨酸的重复蛋白 X1 (NLRX1) 代表了唯一靶向该细胞位置的 NLR 家族成员，这意味着 NLRX1 可能在线粒体功能和细胞生理学之间建立了基本联系。然而，NLRX1 功能在细胞衰老（衰老生物学中的一个关键概念成分）中的重要性尚待确定。在这里，我们证明了与衰老生物学有关的分子标志，包括 NAD ⁺下降和 mTOR、p53 和 p16 ^{INK4A的激活}在体外 NLRX1 缺乏症中显着增强。在体外存在或不存在 NLRX1 的情况下复制性细胞衰老的机制研究表明，缺乏 NLRX1 的成纤维细胞无法维持最佳的 NAD ⁺ /NADH 比率，这会导致 SIRT1 的下降和 mTOR、p16 ^{INK4A的激活}和 p53，导致衰老相关 β-半乳糖苷酶 (SA-β-gal) 阳性细胞的增加。重要的是，在 NLRX1 缺陷中增强的细胞衰老反应通过体外 mTOR 信号传导的药理学抑制显着减弱。最后，我们的体内鼠研究表明，NLRX1 在鼠肺中随着年龄的增长而降低，而体内 NLRX1 缺乏会加速肺功能和结构的变化，这概括了在人类衰老肺中观察到的发现。总之，目前的研究为 NLRX1 作为细胞衰老和体内肺衰老的关键调节因子提供了证据。