Institute of Molecular and Cell Biology, A*STAR Research Entities, Singapore, 138673, Singapore.
Department of Biological Sciences, National University of Singapore, Singapore, 117543, Singapore.
Cell Death Differ. 2021 Apr;28(4):1379-1397. doi: 10.1038/s41418-020-00664-0. Epub 2020 Nov 12.
Motor neurons (MNs) are highly energetic cells and recent studies suggest that altered energy metabolism precede MN loss in amyotrophic lateral sclerosis (ALS), an age-onset neurodegenerative disease. However, clear mechanistic insights linking altered metabolism and MN death are still missing. In this study, induced pluripotent stem cells from healthy controls, familial ALS, and sporadic ALS patients were differentiated toward spinal MNs, cortical neurons, and cardiomyocytes. Metabolic flux analyses reveal an MN-specific deficiency in mitochondrial respiration in ALS. Intriguingly, all forms of familial and sporadic ALS MNs tested in our study exhibited similar defective metabolic profiles, which were attributed to hyper-acetylation of mitochondrial proteins. In the mitochondria, Sirtuin-3 (SIRT3) functions as a mitochondrial deacetylase to maintain mitochondrial function and integrity. We found that activating SIRT3 using nicotinamide or a small molecule activator reversed the defective metabolic profiles in all our ALS MNs, as well as correct a constellation of ALS-associated phenotypes.
运动神经元（MNs）是高度活跃的细胞，最近的研究表明，在肌萎缩侧索硬化症（ALS）中，能量代谢的改变先于 MN 的丧失，ALS 是一种年龄相关性神经退行性疾病。然而，将代谢改变与 MN 死亡联系起来的明确机制仍不清楚。在这项研究中，来自健康对照者、家族性 ALS 和散发性 ALS 患者的诱导多能干细胞被分化为脊髓 MNs、皮质神经元和心肌细胞。代谢通量分析显示 ALS 中 MN 特有的线粒体呼吸缺陷。有趣的是，我们研究中测试的所有形式的家族性和散发性 ALS MN 都表现出相似的代谢缺陷谱，这归因于线粒体蛋白的过度乙酰化。在线粒体中，Sirtuin-3（SIRT3）作为一种线粒体去乙酰化酶，发挥作用以维持线粒体功能和完整性。我们发现，使用烟酰胺或小分子激活剂激活 SIRT3 可逆转我们所有 ALS MN 的代谢缺陷谱，并纠正一系列与 ALS 相关的表型。
