Dataset Information

Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3.

ABSTRACT: Nutrient availability is the major regulator of life and reproduction, and a complex cellular signaling network has evolved to adapt organisms to fasting. These sensor pathways monitor cellular energy metabolism, especially mitochondrial ATP production and NAD(+)/NADH ratio, as major signals for nutritional state. We hypothesized that these signals would be modified by mitochondrial respiratory chain disease, because of inefficient NADH utilization and ATP production. Oral administration of nicotinamide riboside (NR), a vitamin B3 and NAD(+) precursor, was previously shown to boost NAD(+) levels in mice and to induce mitochondrial biogenesis. Here, we treated mitochondrial myopathy mice with NR. This vitamin effectively delayed early- and late-stage disease progression, by robustly inducing mitochondrial biogenesis in skeletal muscle and brown adipose tissue, preventing mitochondrial ultrastructure abnormalities and mtDNA deletion formation. NR further stimulated mitochondrial unfolded protein response, suggesting its protective role in mitochondrial disease. These results indicate that NR and strategies boosting NAD(+) levels are a promising treatment strategy for mitochondrial myopathy.

SUBMITTER: Khan NA

PROVIDER: S-EPMC4203351 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3.

Khan Nahid A NA Auranen Mari M Paetau Ilse I Pirinen Eija E Euro Liliya L Forsström Saara S Pasila Lotta L Velagapudi Vidya V Carroll Christopher J CJ Auwerx Johan J Suomalainen Anu A

EMBO molecular medicine 20140601 6

Nutrient availability is the major regulator of life and reproduction, and a complex cellular signaling network has evolved to adapt organisms to fasting. These sensor pathways monitor cellular energy metabolism, especially mitochondrial ATP production and NAD(+)/NADH ratio, as major signals for nutritional state. We hypothesized that these signals would be modified by mitochondrial respiratory chain disease, because of inefficient NADH utilization and ATP production. Oral administration of nico ...[more]

PMID: 24711540

Similar Datasets

Project description:Purpose: We examined the impact of niacin on muscle gene expression in mitochondrial myopathy patients and healthy controls. Methods: Muscle transcriptomics profiles were generated using global transcriptomics analysis by RNA sequencing which was performed by the Beijing Genomic Institute (BGI) using their standard protocols Results: The pathway enrichment analysis of RNA-sequencing data indicated that phagosome formation, serine/glycine/one-carbon pathways (de novo serine biosynthesis, purine degradation, glutathione metabolism), LXR/RXR activation, eicosanoid, glycoprotein 6, atherosclerosis, iron homeostasis and cAMP-mediated signalling pathways were among the most significantly changed in patients. Only five and two of the disease associated pathways remained significantly changed after 4- and 10-month supplementation, respectively, in patients as compared to controls. The most prominent niacin-related transcriptomic change in patients’ muscle (patient 10-months on niacin vs patient baseline) was wide-spread downregulation of mTOR-dependent cytoplasmic translation, involving a large number of cytoplasmic ribosome subunits as well as translation initiation factor eIF1. In patients, niacin activated also the peroxisome proliferator-activated receptor signaling pathway, known to induce mitochondrial biogenesis. Niacin also led to decreased atherosclerosis signaling including lowered apolipoprotein expression in patients. The healthy control muscles showed only few changes after 4-months of niacin. To examine in detail the effects of NAD-booster niacin in the mitochondrial integrated stress response (ISRmt), we studied the effects NAD+ boosting for the expression of 24 ISRmt target genes in the patients’ muscle. The analysis confirmed wide-spread induction of these genes, but their expression was unaffected by niacin (ATF5 and its targets ASNS, TRIB3, FGF21, GDF15, MTHFD2, and MTHFD1L; de novo synthesis of serine, PSAT1, PHGDH and SHMT2; glutathione metabolism GPX3 and GSR; and unfolded protein response ER CHOP). Conclusions: These results showed that niacin modulated the expression of disease associated pathways and suppressed mTOR signalling in patients but niacin did not affect disease-related ISRmt signalling.

Dataset Information

Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3.

Publications

Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets