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 (MN) 是高能细胞，最近的研究表明，在肌萎缩侧索硬化症 (ALS)（一种老年性神经退行性疾病）中，能量代谢的改变先于 MN 损失。然而，仍然缺少将代谢改变和 MN 死亡联系起来的明确机制见解。在这项研究中，来自健康对照、家族性 ALS 和散发性 ALS 患者的诱导多能干细胞分化为脊髓 MN、皮质神经元和心肌细胞。代谢通量分析揭示了 ALS 中线粒体呼吸的 MN 特异性缺陷。有趣的是，在我们的研究中测试的所有形式的家族性和散发性 ALS MN 都表现出相似的有缺陷的代谢特征，这归因于线粒体蛋白的高度乙酰化。在线粒体中，Sirtuin-3 (SIRT3) 作为线粒体脱乙酰酶发挥作用，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 可以逆转我们所有 ALS MN 中的缺陷代谢谱，并纠正一系列与 ALS 相关的表型。