Journal Article

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

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

2025

Overview

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 (4 mg/kg, i.p.). Then mice received NMN (500 mg/kg, i.p.) or mito-TEMPO (0.7 mg/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 (1 µg/mL) in the presence of NMN (500 µmol/L) or mito-TEMPO (25 nmol/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.

• Publisher: Springer Nature Singapore,Nature Publishing Group
• Subject: Acetylation / Animals / Apoptosis / Autophagy / Autophagy - drug effects / Biomedical and Life Sciences / Biomedicine / Cardiomyocytes / Cardiotonic Agents - pharmacology / Cardiotonic Agents - therapeutic use / Cyclophilins - antagonists & inhibitors / Cyclophilins - metabolism / Cyclosporins / Echocardiography / Heart / Immunology / Internal Medicine / Laboratory animals / Lipopolysaccharides / Lysosomes - drug effects / Lysosomes - metabolism / Male / Medical Microbiology / Membrane permeability / Metabolism / Mice / Mice, Inbred C57BL / Mitochondria, Heart - drug effects / Mitochondria, Heart - metabolism / Mitochondrial permeability transition pore / Mitochondrial Permeability Transition Pore - metabolism / Myocardium - metabolism / Myocardium - pathology / Myocytes, Cardiac - drug effects / Myocytes, Cardiac - metabolism / NAD / Neonates / Nicotinamide Mononucleotide - pharmacology / Oxidation / Oxidative stress / Peptidyl-Prolyl Isomerase F - metabolism / Permeability / Pharmacology/Toxicology / Reactive Oxygen Species - metabolism / Sepsis / Sepsis - complications / Sepsis - drug therapy / Sepsis - metabolism / Vaccine