Nicotinamide riboside promotes Mfn2-mediated mitochondrial fusion in diabetic hearts through the SIRT1-PGC1α-PPARα pathway.

Abstract

Myocardial dysfunction is associated with an imbalance in mitochondrial fusion/fission dynamics in patients with diabetes. However, effective strategies to regulate mitochondrial dynamics in the diabetic heart are still lacking. Nicotinamide riboside (NR) supplementation ameliorated mitochondrial dysfunction and oxidative stress in both cardiovascular and aging-related diseases. This study investigated whether NR protects against diabetes-induced cardiac dysfunction by regulating mitochondrial fusion/fission and further explored the underlying mechanisms. Here, we showed an evident decrease in NAD+ (nicotinamide adenine dinucleotide) levels and mitochondrial fragmentation in the hearts of leptin receptor-deficient diabetic (db/db) mouse models. NR supplementation significantly increased NAD+ content in the diabetic hearts and promoted mitochondrial fusion by elevating Mfn2 level. Furthermore, NR-induced mitochondrial fusion suppressed mitochondrial H2O2 and O2•- production and reduced cardiomyocyte apoptosis in both db/db mice hearts and neonatal primary cardiomyocytes. Mechanistically, chromatin immunoprecipitation (ChIP) and luciferase reporter assay analyses revealed that PGC1α and PPARα interdependently regulated Mfn2 transcription by binding to its promoter region. NR treatment elevated NAD+ levels and activated SIRT1, resulting in the deacetylation of PGC1α and promoting the transcription of Mfn2. These findings suggested the promotion of mitochondrial fusion via oral supplementation of NR as a potential strategy for delaying cardiac complications in patients with diabetes.

• Authors: Lang Hu, Yanjie Guo, Liqiang Song, He Wen, Nan Sun, Ying Wang, Bingchao Qi, Qi Liang, Jing Geng, Xuteng Liu, Feng Fu, Yan Li
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 183 Pg. 75-88 (04 2022) ISSN: 1873-4596 [Electronic] United States
• PMID: 35318101 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Mitochondrial Proteins
• PPAR alpha
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Pyridinium Compounds
• nicotinamide-beta-riboside
• Niacinamide
• Hydrogen Peroxide
• SIRT1 protein, human
• Sirt1 protein, mouse
• Sirtuin 1
• GTP Phosphohydrolases
• MFN2 protein, human
• Mfn2 protein, mouse

Topics

• Animals
• Diabetes Mellitus
• GTP Phosphohydrolases (genetics, metabolism)
• Humans
• Hydrogen Peroxide (metabolism)
• Mice
• Mitochondria, Heart (physiology)
• Mitochondrial Dynamics
• Mitochondrial Proteins (genetics, metabolism)
• Niacinamide (analogs & derivatives, pharmacology)
• PPAR alpha (metabolism)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (genetics, metabolism)
• Pyridinium Compounds
• Sirtuin 1 (genetics, metabolism)