How to Maintain NAD+ Homeostasis to Regulate Mitochondrial and Cardiac Function
1. Introduction
Mitochondria are the center of energy metabolism in cardiomyocytes, which are necessary for maintaining normal myocardial contractility and cardiac function. Typically, the development of cardiovascular disease is usually accompanied by mitochondrial dysfunction. Impaired autophagy is known to cause mitochondrial dysfunction and heart failure, in part due to altered mitophagy and protein quality control. Notably, external replenishment of nicotinamide adenine dinucleotide (NAD+) precursors can enhance autophagy and mitochondrial quality control to maintain metabolic health, thereby regulate mitochondrial and cardiac function.2. NAD+ metabolism in mitochondrial and cardiac function
Cardiomyocytes accumulate NAD+ mostly within their mitochondria, where the bulk of cellular oxidation-reduction reactions occur. However, NAD+ is also present in the cytosol and nucleus, in which NAD+-derived metabolites and NAD+-dependent enzymes contribute to various cellular functions.3. Mitochondrial and cardiac dysfunction induced by NAD+ deficiency
Mitochondrial and cardiac dysfunction triggered by NAD+ deficiency is alleviated in cAtg3-KO mouse hearts post the administration of β-nicotinamide mononucleotide (NMN), as evidenced by the restoration of citrate synthase (CS) activity, partial normalization of ATP level and NPPB mRNA expression in cAtg3-KO mice as well as upregulation of ADP level in WT mouse hearts. Besides, NNMT inhibition can rescue mitochondrial and cardiac dysfunction in cAtg3-KO mice by restoring NAD+ level.
4. The impact of autophagic flux upon cardiac and mitochondrial function
Autophagy is an intracellular degradation pathway that recycles subcellular components, playing a critical in modulating metabolic homeostasis. Autophagic flux, a central homeostatic mechanism that degrades materials toxic to cardiomyocytes, can mediate SQSTM1-NF-κB-NNMT signal transduction to control the cellular level of NAD+, thereby maintaining the mitochondrial and cardiac function.5. Conclusion
Autophagic flux may be a potential way to maintain the cellular level of NAD to regulate mitochondrial and cardiac fiunction..
Reference
[1] Abdellatif M, Sedej S, Kroemer G. NAD+ Metabolism in Cardiac Health, Aging, and Disease. Circulation. 2021;144(22):1795-1817. doi:10.1161/CIRCULATIONAHA.121.056589
[2] Zhang Q, Li Z, Li Q, et al. Control of NAD+ homeostasis by autophagic flux modulates mitochondrial and cardiac function. EMBO J. Published online January 11, 2024. doi:10.1038/s44318-023-00009-w
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