Control of NAD + homeostasis by autophagic flux modulates mitochondrial and cardiac function

Quanjiang Zhang; Zhonggang Li; Qiuxia Li; Samuel Aj Trammell; Mark S Schmidt; Karla Maria Pires; Jinjin Cai; Yuan Zhang; Helena Kenny; Sihem Boudina; Charles Brenner; E Dale Abel

doi:10.1038/s44318-023-00009-w

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Control of NAD + homeostasis by autophagic flux modulates mitochondrial and cardiac function

Journal article

Open access

Peer reviewed

Control of NAD + homeostasis by autophagic flux modulates mitochondrial and cardiac function

Quanjiang Zhang, Zhonggang Li, Qiuxia Li, Samuel Aj Trammell, Mark S Schmidt, Karla Maria Pires, Jinjin Cai, Yuan Zhang, Helena Kenny, Sihem Boudina, …

The EMBO journal, Vol.43(3), pp.362-390

02/01/2024

DOI: 10.1038/s44318-023-00009-w

PMCID: PMC10897141

PMID: 38212381

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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 .

Autophagic Flux

NAD+ Metabolism

Mitochondrial Homeostasis

Heart Dysfunction

Details

Title: Subtitle: Control of NAD + homeostasis by autophagic flux modulates mitochondrial and cardiac function
Creators: Quanjiang Zhang - Department of Internal Medicine, Fraternal Order of Eagles Diabetes Research Center, and Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
Zhonggang Li - University of Utah
Qiuxia Li - University of Iowa
Samuel Aj Trammell - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
Mark S Schmidt - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
Karla Maria Pires - University of Utah
Jinjin Cai - University of Utah
Yuan Zhang - University of Iowa
Helena Kenny - Department of Internal Medicine, Fraternal Order of Eagles Diabetes Research Center, and Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
Sihem Boudina - University of Utah
Charles Brenner - City Of Hope National Medical Center
E Dale Abel - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA. DOMChair_DaleAbel@mednet.ucla.edu
Resource Type: Journal article
Publication Details: The EMBO journal, Vol.43(3), pp.362-390
DOI: 10.1038/s44318-023-00009-w
PMID: 38212381
PMCID: PMC10897141
NLM abbreviation: EMBO J
eISSN: 1460-2075
Grant note: U54 HL112311 / NHLBI NIH HHS
Language: English
Electronic publication date: 01/11/2024
Date published: 02/01/2024
Academic Unit: Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984544956502771

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