The Abimael Laboratory of Neurometabolism, Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Laboratory of Developmental Neurobiology, The Rockefeller University, New York, NY, USA.
The Abimael Laboratory of Neurometabolism, Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Cell Metab. 2024 Jun 4;36(6):1394-1410.e12. doi: 10.1016/j.cmet.2024.05.002.
A vexing problem in mitochondrial medicine is our limited capacity to evaluate the extent of brain disease in vivo. This limitation has hindered our understanding of the mechanisms that underlie the imaging phenotype in the brain of patients with mitochondrial diseases and our capacity to identify new biomarkers and therapeutic targets. Using comprehensive imaging, we analyzed the metabolic network that drives the brain structural and metabolic features of a mouse model of pyruvate dehydrogenase deficiency (PDHD). As the disease progressed in this animal, in vivo brain glucose uptake and glycolysis increased. Propionate served as a major anaplerotic substrate, predominantly metabolized by glial cells. A combination of propionate and a ketogenic diet extended lifespan, improved neuropathology, and ameliorated motor deficits in these animals. Together, intermediary metabolism is quite distinct in the PDHD brain-it plays a key role in the imaging phenotype, and it may uncover new treatments for this condition.
线粒体医学中的一个棘手问题是，我们评估活体大脑疾病程度的能力有限。这种局限性阻碍了我们对导致线粒体疾病患者大脑影像学表型的机制的理解，也阻碍了我们识别新的生物标志物和治疗靶点的能力。我们使用综合影像学分析了丙酮酸脱氢酶缺乏症 (PDHD) 小鼠模型的代谢网络，该网络驱动大脑的结构和代谢特征。随着疾病在这种动物体内的发展，大脑葡萄糖摄取和糖酵解增加。丙酸盐作为一种主要的补充物，主要由神经胶质细胞代谢。丙酸盐和生酮饮食的组合延长了这些动物的寿命，改善了神经病理学，并改善了它们的运动缺陷。总之，PDHD 大脑中的中间代谢非常独特——它在影像学表型中起着关键作用，并且可能为这种疾病开辟新的治疗方法。
