Control of NAD+ homeostasis by autophagic flux modulates mitochondrial and cardiac function
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Control of NAD+ homeostasis by autophagic flux modulates mitochondrial and cardiac function. / Zhang, Quanjiang; Li, Zhonggang; Li, Qiuxia; Trammell, Samuel A.J.; Schmidt, Mark S.; Pires, Karla Maria; Cai, Jinjin; Zhang, Yuan; Kenny, Helena; Boudina, Sihem; Brenner, Charles; Abel, E. Dale.
In: EMBO Journal, Vol. 43, No. 3, 2024, p. 362-390.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Control of NAD+ homeostasis by autophagic flux modulates mitochondrial and cardiac function
AU - Zhang, Quanjiang
AU - Li, Zhonggang
AU - Li, Qiuxia
AU - Trammell, Samuel A.J.
AU - Schmidt, Mark S.
AU - Pires, Karla Maria
AU - Cai, Jinjin
AU - Zhang, Yuan
AU - Kenny, Helena
AU - Boudina, Sihem
AU - Brenner, Charles
AU - Abel, E. Dale
PY - 2024
Y1 - 2024
N2 - 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+.
AB - 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+.
KW - Autophagic Flux
KW - Heart Dysfunction
KW - Mitochondrial Homeostasis
KW - NAD Metabolism
U2 - 10.1038/s44318-023-00009-w
DO - 10.1038/s44318-023-00009-w
M3 - Journal article
C2 - 38212381
AN - SCOPUS:85184138475
VL - 43
SP - 362
EP - 390
JO - E M B O Journal
JF - E M B O Journal
SN - 0261-4189
IS - 3
ER -
ID: 384413468