2024年12月2日，加拿大韦仕敦大学Tian-qing Peng等研究人员合作在《中国药理学报》杂志在线发表论文。该研究发现烟酰胺单核苷酸通过防止亲环素F修饰和溶酶体功能障碍，保护小鼠的败血症性心脏。

研究人员表示，心肌功能障碍是败血症患者死亡的决定性因素。环孢素F（PPIF）是线粒体通透性转变孔（mPTP）的主要组成部分，并作为mPTP的敏感因子，触发mPTP的开放。在败血症中，NAD⁺水平下降会损害Sirtuin 3的功能，这可能会阻止PPIF的去乙酰化。通过烟酰胺单核苷酸（NMN）补充NAD⁺可以减轻小鼠的败血症性心肌功能障碍。此外，使用mPTP抑制剂亲环素A（cyclosporine-A）能够减轻败血症引起的心肌功能障碍，而缺失PPIF则减少了败血症中的肺脏和肝脏损伤，从而提高了存活率。有理由认为，通过NMN补充NAD⁺，可能通过PPIF去乙酰化和/或抑制线粒体ROS介导的PPIF氧化，来预防mPTP开放，从而保护败血症性心脏。

研究人员探讨了NMN如何缓解小鼠的败血症性心肌功能障碍。败血症通过注射LPS（4 mg/kg，腹腔注射）在小鼠中诱导。随后小鼠在LPS注射后立即接受NMN（500 mg/kg，腹腔注射）或mito-TEMPO（0.7 mg/kg，腹腔注射），并进行超声心动图检查以评估心肌功能。实验结束时，收集心脏组织和血清进行分析。在体外实验中，将新生小鼠心肌细胞与LPS（1 µg/mL）和NMN（500 µmol/L）或mito-TEMPO（25 nmol/L）共同处理。

结果显示，LPS处理显著增加了线粒体ROS的产生，并诱导了心肌细胞和小鼠心脏中的溶酶体功能障碍和异常自噬，导致了炎症反应以及败血症小鼠的心肌损伤和功能障碍。NMN的应用减轻了LPS引起的不良影响。使用mito-TEMPO选择性抑制线粒体超氧化物的生成，减轻了败血症小鼠心脏中的溶酶体功能障碍和异常自噬。值得注意的是，LPS处理显著增加了PPIF的乙酰化和氧化，而NMN则在小鼠心脏中预防了这一过程。敲低PPIF复制了NMN或mito-TEMPO在ROS生成、溶酶体功能障碍、异常自噬和心肌损伤/功能障碍中的有益作用。此外，NMN的应用还抑制了LPS引起的ATP5A1乙酰化，并增加了ATP5A1蛋白水平和败血症小鼠心脏中的ATP生成。

该研究表明，NMN通过调节线粒体ROS和PPIF之间的相互作用，在维持正常的溶酶体功能和自噬、保护ATP5A1以及ATP生成方面发挥作用，从而保护败血症中的心脏。

附：英文原文

Title: Nicotinamide mononucleotide protects septic hearts in mice via preventing cyclophilin F modification and lysosomal dysfunction

Author: Ni, Rui, Ji, Xiao-yun, Cao, Ting, Liu, Xiu-wen, Wang, Chao, Lu, Chao, Peng, Angel, Zhang, Zhu-xu, Fan, Guo-Chang, Zhang, Jin, Su, Zhao-liang, Peng, Tian-qing

Issue&Volume: 2024-12-02

Abstract: Myocardial dysfunction is a decisive factor of death in septic patients. Cyclophilin F (PPIF) is a major component of the mitochondrial permeability transition pore (mPTP) and acts as a critical mPTP sensitizer triggering mPTP opening. In sepsis, decreased NAD+ impairs Sirtuin 3 function, which may prevent PPIF de-acetylation. Repletion of NAD+ with nicotinamide mononucleotide (NMN) reduces myocardial dysfunction in septic mice. In addition, administration of the mPTP inhibitor cyclosporine-A attenuated sepsis-induced myocardial dysfunction, and deletion of PPIF reduced lung and liver injuries in sepsis, leading to increased survival. It is plausible that NAD+ repletion with NMN may prevent mPTP opening in protecting septic hearts through PPIF de-acetylation and/or inhibition of mitochondrial ROS-mediated PPIF oxidation. In this study we investigated how NMN alleviated myocardial dysfunction in septic mice. Sepsis was induced in mice by injection of LPS (4mg/kg, i.p.). Then mice received NMN (500mg/kg, i.p.) or mito-TEMPO (0.7mg/kg, i.p.) right after LPS injection, and subjected to echocardiography for assessing myocardial function. At the end of experiment, the heart tissues and sera were collected for analyses. In vitro experiments were conducted in neonatal mouse cardiomyocytes treated with LPS (1μg/mL) in the presence of NMN (500μmol/L) or mito-TEMPO (25nmol/L). We showed that LPS treatment markedly increased mitochondrial ROS production and induced lysosomal dysfunction and aberrant autophagy in cardiomyocytes and mouse hearts, leading to inflammatory responses and myocardial injury and dysfunction in septic mice. NMN administration attenuated LPS-induced deteriorative effects. Selective inhibition of mitochondrial superoxide production with mito-TEMPO attenuated lysosomal dysfunction and aberrant autophagy in septic mouse hearts. Notably, LPS treatment significantly increased acetylation and oxidation of PPIF, which was prevented by NMN in mouse hearts. Knockdown of PPIF replicated the beneficial effects of NMN or mito-TEMPO on ROS production, lysosomal dysfunction, aberrant autophagy, and myocardial injury/dysfunction in sepsis. In addition, administration of NMN abrogated LPS-induced ATP5A1 acetylation and increased ATP5A1 protein levels and ATP production in septic mouse hearts. This study demonstrates that NMN modulates the interplay of mitochondrial ROS and PPIF in maintaining normal lysosomal function and autophagy and protecting ATP5A1 and ATP production during sepsis.

DOI: 10.1038/s41401-024-01424-3

Source: https://www.nature.com/articles/s41401-024-01424-3