Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich's ataxia cardiomyopathy model
Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich's ataxia cardiomyopathy model
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DOI：
10.1172/jci.insight.93885
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发表时间：
2017-07-20
期刊：
影响因子：
8
通讯作者：
Hirschey, Matthew D.
中科院分区：
文献类型：
--
作者：
Martin, Angelical S.;Abraham, Dennis M.;Hirschey, Matthew D.
通过补充前体烟酰胺单核苷酸（NMN）提高NAD(+)水平可改善多种疾病小鼠模型的心脏功能。虽然NMN影响线粒体代谢的多个方面，但NAD(+)增加增强心脏功能的分子机制尚不清楚。一种可能的NAD(+)治疗作用机制是通过激活线粒体NAD(+)依赖性蛋白去乙酰化酶Sirtuin 3（SIRT3）实现的。我们评估了NMN的治疗效果以及SIRT3在弗里德赖希共济失调心肌病小鼠模型（FXN - KO）中的作用。在基线水平，FXN - KO心脏存在线粒体蛋白过度乙酰化、Sirt3 mRNA表达降低以及NAD(+)补救途径增强的迹象。值得注意的是，给予FXN - KO小鼠NMN可使心脏功能恢复到接近正常水平。为了确定SIRT3是否为NMN治疗效果所必需，我们构建了SIRT3 - KO和SIRT3 - KO/FXN - KO（双敲除[dKO]）模型。在FXN - KO中NMN治疗对心脏功能的改善在dKO模型中消失，这表明NMN的作用依赖于心脏SIRT3。与心脏保护相结合，SIRT3介导了NMN诱导的心脏和心脏外代谢功能以及能量代谢的改善。综上所述，这些结果为弗里德赖希共济失调患者补充NMN或进行SIRT3激活剂治疗提供了重要的临床前数据。
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.