Nicotinamide mononucleotide alters mitochondrial dynamics by SIRT3-dependent mechanism in male mice
Nicotinamide mononucleotide alters mitochondrial dynamics by SIRT3-dependent mechanism in male mice
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DOI：
10.1002/jnr.24397
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发表时间：
2019-08-01
影响因子：
4.2
通讯作者：
Kristian, Tibor
中科院分区：
文献类型：
--
作者：
Klimova, Nina;Long, Aaron;Kristian, Tibor
烟酰胺腺嘌呤二核苷酸（NAD（+））是一种重要的信号分子和酶辅因子，参与多种基本的生物学过程。NAD（+）水平随着年龄、神经退行性疾病、急性脑损伤以及肥胖或糖尿病而下降。NAD（+）的缺失导致线粒体和细胞功能受损。给予NAD（+）前体烟酰胺单甘肽（NMN）已显示出改善线粒体生物能量学，逆转年龄相关的生理衰退，并抑制缺血后NAD（+）降解和细胞死亡。在这项研究中，我们确定了NAD（+）代谢和线粒体动力学之间的新联系。单剂量（62.5 mg/kg）的NMN，给予雄性小鼠，增加海马线粒体NAD（+）池长达24小时治疗后，并驱动sirtuin 3（SIRT 3）介导的线粒体蛋白乙酰化的整体下降。这导致海马活性氧水平通过SIRT 3驱动的线粒体锰超氧化物歧化酶的脱乙酰化而降低。因此，由于磷酸化分裂蛋白、动力蛋白相关蛋白1（pDrp 1 [S616]）与线粒体的相互作用较低，神经元中的线粒体碎片化程度较低。总之，NMN对线粒体NAD（+）水平的操纵导致代谢变化，保护线粒体免受活性氧和过度片段化的影响，为病理生理应激条件提供了治疗方法。
Nicotinamide adenine dinucleotide (NAD(+)) is a central signaling molecule and enzyme cofactor that is involved in a variety of fundamental biological processes. NAD(+) levels decline with age, neurodegenerative conditions, acute brain injury, and in obesity or diabetes. Loss of NAD(+) results in impaired mitochondrial and cellular functions. Administration of NAD(+) precursor, nicotinamide mononucleotide (NMN), has shown to improve mitochondrial bioenergetics, reverse age-associated physiological decline, and inhibit postischemic NAD(+) degradation and cellular death. In this study, we identified a novel link between NAD(+) metabolism and mitochondrial dynamics. A single dose (62.5 mg/kg) of NMN, administered to male mice, increases hippocampal mitochondria NAD(+) pools for up to 24 hr posttreatment and drives a sirtuin 3 (SIRT3)-mediated global decrease in mitochondrial protein acetylation. This results in a reduction of hippocampal reactive oxygen species levels via SIRT3-driven deacetylation of mitochondrial manganese superoxide dismutase. Consequently, mitochondria in neurons become less fragmented due to lower interaction of phosphorylated fission protein, dynamin-related protein 1 (pDrp1 [S616]), with mitochondria. In conclusion, manipulation of mitochondrial NAD(+) levels by NMN results in metabolic changes that protect mitochondria against reactive oxygen species and excessive fragmentation, offering therapeutic approaches for pathophysiologic stress conditions.