Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China.
Tianjin Medical University, Tianjin 300070, China.
Exp Biol Med (Maywood). 2022 Jul;247(14):1264-1276. doi: 10.1177/15353702221094235. Epub 2022 May 10.
Mitochondria need to interact with the nucleus under homeostasis and stress to maintain cellular demands and nuclear transcriptional programs. Disrupted mitonuclear interaction is involved in many disease processes. However, the role of mitonuclear signaling regulators in endotoxin-induced acute lung injury (ALI) remains unknown. Nicotinamide adenine dinucleotide (NAD) is closely related to mitonuclear interaction with its central role in mitochondrial metabolism. In the current study, C57BL/6J mice were administrated with lipopolysaccharide 15 mg/kg to induce endotoxin-induced ALI and investigated whether the NAD precursor nicotinamide mononucleotide (NMN) could preserve mitonuclear interaction and alleviate ALI. After pretreatment with NMN for 7 days, NAD levels in the mitochondrial, nucleus, and total intracellular were significantly increased in endotoxemia mice. Moreover, supplementation of NMN alleviated lung pathologic injury, reduced ROS levels, increased MnSOD activities, mitigated mitochondrial dysfunction, ameliorated the defects in the nucleus morphology, and these cytoprotective effects were accompanied by preserving mitonuclear interaction (including mitonuclear protein imbalance and the mitochondrial unfolded protein response, UPR). Furthermore, NAD-mediated mitonuclear protein imbalance and UPR are probably regulated by deacetylase Sirtuin1 (SIRT1). Taken together, our results indicated that NMN pretreatment ameliorated ALI by inducing mitonuclear protein imbalance and activating the UPR in an SIRT1-dependent manner.
线粒体在维持细胞需求和核转录程序的稳态和应激下需要与核相互作用。线粒体-核相互作用的破坏与许多疾病过程有关。然而，线粒体-核信号调节剂在内毒素诱导的急性肺损伤（ALI）中的作用尚不清楚。烟酰胺腺嘌呤二核苷酸（NAD）与线粒体-核相互作用密切相关，其在线粒体代谢中的核心作用。在本研究中，C57BL/6J 小鼠给予脂多糖 15mg/kg 诱导内毒素诱导的 ALI，并研究 NAD 前体烟酰胺单核苷酸（NMN）是否可以维持线粒体-核相互作用并减轻 ALI。NMN 预处理 7 天后，内毒素血症小鼠的线粒体、核和总细胞内 NAD 水平显著升高。此外，NMN 的补充减轻了肺病理损伤，降低了 ROS 水平，增加了 MnSOD 活性，减轻了线粒体功能障碍，改善了核形态缺陷，这些细胞保护作用伴随着维持线粒体-核相互作用（包括线粒体-核蛋白失衡和线粒体未折叠蛋白反应，UPR）。此外，NAD 介导的线粒体-核蛋白失衡和 UPR 可能受去乙酰化酶 Sirtuin1（SIRT1）调节。总之，我们的结果表明，NMN 预处理通过诱导线粒体-核蛋白失衡和以 SIRT1 依赖的方式激活 UPR 来改善 ALI。
