Molecular Neurology, Research Programs Unit, University of Helsinki, Helsinki, Finland.
Molecular Neurology, Research Programs Unit, University of Helsinki, Helsinki, Finland Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
EMBO Mol Med. 2014 Jun;6(6):721-31. doi: 10.1002/emmm.201403943.
Nutrient availability is the major regulator of life and reproduction, and a complex cellular signaling network has evolved to adapt organisms to fasting. These sensor pathways monitor cellular energy metabolism, especially mitochondrial ATP production and NAD(+)/NADH ratio, as major signals for nutritional state. We hypothesized that these signals would be modified by mitochondrial respiratory chain disease, because of inefficient NADH utilization and ATP production. Oral administration of nicotinamide riboside (NR), a vitamin B3 and NAD(+) precursor, was previously shown to boost NAD(+) levels in mice and to induce mitochondrial biogenesis. Here, we treated mitochondrial myopathy mice with NR. This vitamin effectively delayed early- and late-stage disease progression, by robustly inducing mitochondrial biogenesis in skeletal muscle and brown adipose tissue, preventing mitochondrial ultrastructure abnormalities and mtDNA deletion formation. NR further stimulated mitochondrial unfolded protein response, suggesting its protective role in mitochondrial disease. These results indicate that NR and strategies boosting NAD(+) levels are a promising treatment strategy for mitochondrial myopathy.
营养物质的可利用性是生命和繁殖的主要调节因素，一个复杂的细胞信号网络已经进化到可以使生物体适应禁食。这些传感器途径监测细胞能量代谢，特别是线粒体 ATP 产生和 NAD(+)/NADH 比，作为营养状态的主要信号。我们假设这些信号会被线粒体呼吸链疾病改变，因为 NADH 的利用和 ATP 的产生效率低下。先前的研究表明，烟酰胺核糖（NR），一种维生素 B3 和 NAD(+)前体，可提高 NAD(+)水平，并诱导小鼠的线粒体生物发生。在这里，我们用 NR 治疗线粒体肌病小鼠。这种维生素通过在骨骼肌和棕色脂肪组织中强烈诱导线粒体生物发生，有效地延迟了疾病的早晚期进展，防止了线粒体超微结构异常和 mtDNA 缺失的形成。NR 进一步刺激了线粒体未折叠蛋白反应，表明其在线粒体疾病中的保护作用。这些结果表明，NR 和提高 NAD(+)水平的策略是治疗线粒体肌病的一种很有前途的治疗策略。
