烟酰胺单核苷酸
自噬
NAD+激酶
粒体自噬
烟酰胺腺嘌呤二核苷酸
生物
烟酰胺
线粒体
细胞生物学
焊剂(冶金)
生物化学
酶
化学
细胞凋亡
有机化学
作者
Quan‐Jiang Zhang,Zhonggang Li,Qiuxia Li,Samuel A.J. Trammell,Mark S. Schmidt,Karla Maria Pereira Pires,Jinjin Cai,Yuan Zhang,Helena Kenny,Sihem Boudina,Charles Brenner,E. Dale Abel
标识
DOI:10.1038/s44318-023-00009-w
摘要
Abstract Impaired autophagy is known to cause mitochondrial dysfunction and heart failure, in part due to altered mitophagy and protein quality control. However, whether additional mechanisms are involved in the development of mitochondrial dysfunction and heart failure in the setting of deficient autophagic flux remains poorly explored. Here, we show that impaired autophagic flux reduces nicotinamide adenine dinucleotide (NAD + ) availability in cardiomyocytes. NAD + deficiency upon autophagic impairment is attributable to the induction of nicotinamide N-methyltransferase (NNMT), which methylates the NAD + precursor nicotinamide (NAM) to generate N-methyl-nicotinamide (MeNAM). The administration of nicotinamide mononucleotide (NMN) or inhibition of NNMT activity in autophagy-deficient hearts and cardiomyocytes restores NAD + levels and ameliorates cardiac and mitochondrial dysfunction. Mechanistically, autophagic inhibition causes the accumulation of SQSTM1, which activates NF-κB signaling and promotes NNMT transcription. In summary, we describe a novel mechanism illustrating how autophagic flux maintains mitochondrial and cardiac function by mediating SQSTM1-NF-κB-NNMT signaling and controlling the cellular levels of NAD + .
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