NMN-administration forbedrer hjertesvigt på grund af mitokondriel dysfunktion

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 forbedrer lysosomfunktionen og reducerer hjertesvigt hos mus med mitokondriedysfunktion

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 Figur 1)

Figur 1 

2. NMN-administration reducerer ferroptose i hjertet

NMN-administration reducerede ferroptose i hjertet, som er en form for celledød forårsaget af ophobning af jern og lipidperoxidation. Denne reduktion i ferroptose var forbundet med en stigning i glutathionperoxidase 4 (GPX4)-ekspression, som er et nøgleenzym involveret i forebyggelse af lipidperoxidation. Disse fund antyder, at administration af NMN kan beskytte mod hjertesvigt ved at reducere ferroptose i hjertet.

Figur 2

3. NMN-administration genopretter genekspression i hjertet

Studiet viste, at administration af NMN genoprettede udtrykket af flere gener i hjertet, som var nedreguleret hos mus med mitokondrie-dysfunktion. Disse gener er involveret i forskellige cellulære processer, herunder mitokondriefunktion, oxidativt stress og inflammation. Disse fund antyder, at administration af NMN kan forbedre hjertefunktionen ved at genoprette genekspression i hjertet.

Figur 3

4. NMN-administration forbedrer mitokondriefunktionen i hjertet

Studiet viste, at administration af NMN forbedrede mitokondriefunktionen i hjertet, hvilket ses ved en stigning i antallet af mitokondrie-DNA-kopier og ekspressionen af gener involveret i mitokondriebiogenesen. Disse fund antyder, at administration af NMN kan beskytte mod hjertesvigt ved at forbedre mitokondriefunktionen i hjertet.

Figur 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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