Short-term administration of Nicotinamide Mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure.
Short-term administration of Nicotinamide Mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure.
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DOI：
10.1016/j.yjmcc.2017.09.001
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发表时间：
2017-11
影响因子：
5
通讯作者：
Liao X
中科院分区：
文献类型：
--
作者：
Zhang R;Shen Y;Zhou L;Sangwung P;Fujioka H;Zhang L;Liao X
心力衰竭与线粒体功能障碍有关，因此恢复或改善线粒体健康具有治疗重要性。最近，NAD⁺水平的降低以及NAD⁺介导的去乙酰化酶活性已被确认为线粒体功能的负调节因子。利用一种对压力敏感的心脏特异性KLF4缺陷小鼠品系，我们发现应激前心脏中线粒体蛋白过度乙酰化，同时伴有Sirt3和NAD⁺水平降低，这表明KLF4缺陷的心脏易发生与NAD⁺相关的缺陷。此外，我们证明了短期给予烟酰胺单核苷酸（NMN）成功地保护了突变小鼠免受压力过载诱导的心力衰竭。从机制上讲，我们表明NMN保留了线粒体的超微结构，减少了活性氧（ROS）并防止了心脏中的细胞死亡。在培养的心肌细胞中，尽管NMN处理对丙酮酸氧化没有直接影响，但它显著增加了长链脂肪酸氧化。总之，这些结果提供了有力的证据，表明线粒体蛋白过度乙酰化在心脏疾病的发病机制中至关重要，并且给予NMN可能是一种有前途的治疗方法。
Heart failure is associated with mitochondrial dysfunction so that restoring or improving mitochondrial health is of therapeutic importance. Recently, reduction in NAD+ levels and NAD+-mediated deacetylase activity has been recognized as negative regulators of mitochondrial function. Using a cardiac specific KLF4 deficient mouse line that is sensitive to stress, we found mitochondrial protein hyperacetylation coupled with reduced Sirt3 and NAD+ levels in the heart before stress, suggesting that the KLF4-deficient heart is predisposed to NAD+-associated defects. Further, we demonstrated that short-term administration of Nicotinamide Mononucleotide (NMN) successfully protected the mutant mice from pressure overload-induced heart failure. Mechanically, we showed that NMN preserved mitochondrial ultrastructure, reduced ROS and prevented cell death in the heart. In cultured cardiomyocytes, NMN treatment significantly increased long-chain fatty acid oxidation despite no direct effect on pyruvate oxidation. Collectively, these results provide cogent evidence that hyperacetylation of mitochondrial proteins is critical in the pathogenesis of cardiac disease and that administration of NMN may serve as a promising therapy.
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DOI：
10.1016/j.bbamcr.2012.08.015
发表时间：
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影响因子：
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