Mutations in mitochondrial DNA (mtDNA), typically maternally inherited, can result in severe neurological conditions. There is currently no cure for mitochondrial DNA diseases and treatments focus on management of the symptoms rather than correcting the defects downstream of the mtDNA mutation. Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is one such mitochondrial disease that affects many bodily systems, particularly the central nervous system and skeletal muscles. Given the motor deficits seen in MELAS patients, we investigate the contribution of motor neuron pathology to MELAS. Using a spinal cord organoid system derived from induced pluripotent stem cells of a MELAS patient, as well as its isogenically corrected control, we found that high levels of Notch signaling underlie neurogenesis delays and neurite outgrowth defects that are associated with MELAS neural cultures. Furthermore, we demonstrate that the gamma-secretase inhibitor DAPT can reverse these neurodevelopmental defects.

线粒体DNA（mtDNA）的突变（通常是母体遗传）会导致严重的神经系统疾病。目前尚无线粒体DNA疾病的治疗方法，治疗的重点是症状的管理，而不是纠正mtDNA突变下游的缺陷。线粒体脑病，乳酸性酸中毒和中风样发作（MELAS）就是一种线粒体疾病，它影响许多身体系统，尤其是中枢神经系统和骨骼肌。给定在MELAS患者中看到的运动缺陷，我们研究了运动神经元病理对MELAS的贡献。使用源自MELAS患者的诱导性多能干细胞的脊髓类器官系统及其经等基因校正的对照，我们发现，Notch信号的高水平是与MELAS神经文化相关的神经发生延迟和神经突生长缺陷的基础。此外，我们证明，γ-分泌酶抑制剂DAPT可以逆转这些神经发育缺陷。