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

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 un-derlying 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 center dot (-) production and reduced cardiomyocyte apoptosis in both db/db mice hearts and neonatal primary car-diomyocytes. Mechanistically, chromatin immunoprecipitation (ChIP) and luciferase reporter assay analyses revealed that PGC1 alpha and PPAR alpha interdependently regulated Mfn2 transcription by binding to its promoter region. NR treatment elevated NAD+ levels and activated SIRT1, resulting in the deacetylation of PGC1 alpha 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.

Automated summary

In patients with diabetes, myocardial dysfunction is associated with an imbalance in mitochondrial fusion/fission dynamics. Nicotinamide riboside (NR) supplementation can ameliorate mitochondrial dysfunction and oxidative stress by promoting mitochondrial fusion. This study suggests that promoting mitochondrial fusion through oral supplementation of NR could be a potential strategy for delaying cardiac complications in patients with diabetes.