PXD006754

PXD006754 is an original dataset announced via ProteomeXchange.

Title	Nicotinamide Mononucleotide Requires SIRT3 to Improve Cardiac Function and Bioenergetics in a Friedreich’s Ataxia Cardiomyopathy Model
Description	Martin et al. JCI Insigh (2017). Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. While NMN influences several aspects of mitochondrial metabolism, the molecular mechanisms by which increased NAD+ enhances cardiac function are poorly understood. A putative mechanism of NAD+ therapeutic action is via activation of the mitochondrial NAD+-dependent protein deacetylase sirtuin 3 (SIRT3). We assessed the therapeutic efficacy of NMN and the role of SIRT3 in the Friedreich’s Ataxia cardiomyopathy mouse model (FXNKO). At baseline, the FXNKO heart has mitochondrial protein hyperacetylation, reduced Sirt3 mRNA expression, and evidence of increased NAD+ salvage. Remarkably, NMN administered to FXNKO mice restores cardiac function to near-normal levels. To determine whether SIRT3 is required for NMN therapeutic efficacy, we generated SIRT3KO and SIRT3KO/FXNKO (dKO) knockout models. The improvement in cardiac function upon NMN treatment in the FXNKO is lost in the dKO model, demonstrating that the effects of NMN are dependent upon cardiac SIRT3. Coupled with cardio- protection, SIRT3 mediates NMN-induced improvements in both cardiac and extra-cardiac metabolic function and energy metabolism. Taken together, these results serve as important preclinical data for NMN supplementation or SIRT3 activator therapy in Friedreich’s Ataxia patients.
HostingRepository	PRIDE
AnnounceDate	2017-07-21
AnnouncementXML	Submission_2017-07-21_00:43:01.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Angelical Martin
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	acetylated residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2017-06-20 01:39:12	ID requested
⏵ 1	2017-07-21 00:43:02	announced

Martin AS, Abraham DM, Hershberger KA, Bhatt DP, Mao L, Cui H, Liu J, Liu X, Muehlbauer MJ, Grimsrud PA, Locasale JW, Payne RM, Hirschey MD, Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich's ataxia cardiomyopathy model. JCI Insight, 2(14):(2017) [pubmed]

curator keyword: Biomedical

submitter keyword: Acetylation, SIRT3, NMN, Heart Failure, Friedreich’s Ataxia

Matthew D. Hirschey
contact affiliation	Assistant Professor Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition Department of Pharmacology and Cancer Biology Duke University Medical Center
contact email	matthew.hirschey@duke.edu
lab head
Angelical Martin
contact affiliation	Duke University
contact email	angelical.martin@duke.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD006754
     1. Label: PRIDE project
     2. Name: Nicotinamide Mononucleotide Requires SIRT3 to Improve Cardiac Function and Bioenergetics in a Friedreich’s Ataxia Cardiomyopathy Model