NMN administration improves heart failure because of mitochondrial dysfunction

Myocardial mitochondria are primary sites of myocardial energy metabolism. Mitochondrial disorders are associated with various cardiac diseases. Mitochondrial translation defects cause not only mitochondrial dysfunction but also decreased nicotinamide adenine dinucleotide (NAD+ ) levels, leading to impaired lysosomal acidification and autophagy. In this study, reseachers investigated whether nicotinamide mononucleotide (NMN) administration, which compensates for decreased NAD+ levels, improves heart failure because of mitochondrial dysfunction. NMN administration reduced damaged lysosomes and improved autophagy, thereby reducing heart failure and extending the lifespan in p32cKO mice. The study found that lysosomal damage due to mitochondrial dysfunction induced ferroptosis, involving the accumulation of iron in lysosomes and lipid peroxide.

1. NMN administration improves lysosomal function and reduces heart failure in mice with mitochondrial dysfunction

The study found that NMN administration improved lysosomal function and reduced heart failure in mice with mitochondrial dysfunction. Specifically, NMN supplementation reduced damaged lysosomes and improved autophagy, leading to a reduction in heart failure and an extension of lifespan in these mice. These findings suggest that NMN supplementation strongly affects lysosomal function, offering a potential therapeutic approach for heart failure.(as shown in Figure 1)

Figure 1 

2. NMN administration reduces ferroptosis in the heart

NMN administration reduced ferroptosis in the heart, which is a form of cell death caused by the accumulation of iron and lipid peroxidation. This reduction in ferroptosis was associated with an increase in glutathione peroxidase 4 (GPX4) expression, which is a key enzyme involved in the prevention of lipid peroxidation. These findings suggest that NMN administration may protect against heart failure by reducing ferroptosis in the heart.

Figure 2

3. NMN administration restores gene expression in the heart

The study found that NMN administration restored the expression of several genes in the heart that were downregulated in mice with mitochondrial dysfunction. These genes are involved in various cellular processes, including mitochondrial function, oxidative stress, and inflammation. These findings suggest that NMN administration may improve heart function by restoring gene expression in the heart.

Figure 3

4. NMN administration improves mitochondrial function in the heart

The study found that NMN administration improved mitochondrial function in the heart, as evidenced by an increase in mitochondrial DNA copy number and the expression of genes involved in mitochondrial biogenesis. These findings suggest that NMN administration may protect against heart failure by improving mitochondrial function in the heart.

Figure 4

Mitochondria are the main organelles for energy production, and mitochondrial dysfunction causes serious diseases associated with aging. We previously found that (1) the expression of NAD+ synthase expression was decreased owing to mitochondrial dysfunction and lysosomal and autophagic function was impaired owing to decreased NAD+ biosynthesis (Yagi et al, 2021) as an additional cause of the exacerbation of chronic heart failure associated with aging. This study shows that NMN administration improves lysosomal function and cell death by ferroptosis when NAD+ levels are improved. In the near future, we aimed to apply NMN to clinical use in aging- and lysosome-related diseases.

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