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Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model
Open accessAbstract
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 exists 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 (FXN-KO). At baseline, the FXN-KO heart has mitochondrial protein hyperacetylation, reduced Sirt3 mRNA expression, and evidence of increased NAD + salvage. Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels. To determine whether SIRT3 is required for NMN therapeutic efficacy, we generated SIRT3-KO and SIRT3-KO/FXN-KO (double KO [dKO]) models. The improvement in cardiac function upon NMN treatment in the FXN-KO 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 extracardiac 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.
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“SIRT3 mediates NMN-induced improvements in cardiac and extracardiac metabolic function in a mouse model of cardiomyopathy207.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [207]
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Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation
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Self-citationCardiac Metabolism in Heart Failure
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- 10.1016/j.celrep.2015.09.023 · DOI
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Metadata
- Authors
- Martin, A. S., Abraham, D. M., Hershberger, K. A., Bhatt, D. P., Mao, L., Cui, H., Liu, J., Liu, X., Muehlbauer, M. J., Grimsrud, P. A., Locasale, J. W., Payne, R. M., & Hirschey, M. D.
- Affiliations
- Duke University (US)
- Department of Pharmacology and Cancer Biology,
- Indiana University Indianapolis (US)
- ORCID
- Venue
- JCI Insight
- Published
- 2017-07-20
- Volume
- 2
- Issue
- 14
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC5518566
- OpenAlex
- W2736952832
- Cited by
- 128
- References
- 69
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 16 · 2023: 17 · 2022: 22 · 2021: 18 · 2020: 11 · 2019: 11 · 2018: 15 · 2017: 3
- FWCI
- 6.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- JCI Insight (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- Friedreich's Ataxia Research Alliance
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (R01AA022146)
- National Heart, Lung, and Blood Institute (F31HL123275, K08HL125905)
- National Cancer Institute (R00CA168997)
- National Institute of General Medical Sciences (T32GM007184, T32GM007105)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK096493)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- nicotinamide mononucleotide, SIRT3, cardiac function, myocardial energy metabolism, mitochondrial metabolism, NAD+ supplementation
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