Improving lysosomal ferroptosis with NMN administration protects against heart failure

Abstract

Myocardial mitochondria are primary sites of myocardial energy metabolism. Mitochondrial disorders are associated with various cardiac diseases. We previously showed that mice with cardiomyocyte-specific knockout of the mitochondrial translation factor p32 developed heart failure from dilated cardiomyopathy. 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, we 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. We found that lysosomal damage due to mitochondrial dysfunction induced ferroptosis, involving the accumulation of iron in lysosomes and lipid peroxide. The ameliorative effects of NMN supplementation were found to strongly affect lysosomal function rather than mitochondrial function, particularly lysosome-mediated ferroptosis. NMN supplementation can improve lysosomal, rather than mitochondrial, function and prevent chronic heart failure.

Preventing the Fatty Acid-Transporter CD36 From Taking its Toll on the Heart

“…NMN had already been shown by others to reduce lysosome ferroptosis, an iron-dependent cell death reported to involve mitochondria in HF. 14 Whether reduction of ferroptosis and/or recovery of NAD signaling pathways, such as sirtuins deacetylases, are also playing a role in the effects of NMN to reduce HFD-induced lipotoxicity, remains to be determined. Interestingly, from a clinical perspective, NMN and more often nicotinamide riboside have already been tested in various clinical trials with patients with mild metabolic disorders or aged but still in good health, although with somewhat lower benefits than expected from preclinical research results as regards systemic parameters such as insulin resistance or body weight loss but rather positive results in the reduction of inflammatory markers.…”