Hegde Vijay R, Vogel Rutger, Feany Mel B
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, NRB 650, 77 Ave Louis Pasteur, Boston, MA 02115, USA.
Department of Cell Biology, Harvard Medical School, Boston, MA 02130, USA.
Hum Mol Genet. 2014 Sep 1;23(17):4686-92. doi: 10.1093/hmg/ddu188. Epub 2014 Apr 23.
Mitochondrial electron transport chain (ETC) disorders cause severe neurological disease, typically in the context of fatal encephalomyelopathies. Neuronal cell autonomous energy deficiency due to reduced mitochondrial adenosine triphosphate production is currently the leading hypothesis to explain the neurotoxicity in ETC disorders. To define the mechanisms underlying neuropathology in ETC disorders, we have modeled the most common type of ETC disorder, complex I deficiency, in Drosophila. Our model recapitulates important clinical features of the disease including neuronal loss, mitochondrial enlargement, motor dysfunction and early death. Using cell-type specific gene knockdown, we find that both neurons and glia contribute to the disease phenotype and that glia play a critical non-cell autonomous role in the development of neuronal toxicity. Our results open up an unexpected avenue of research, and could lead to the development of new treatment strategies.
线粒体电子传递链（ETC）紊乱会引发严重的神经疾病，通常发生在致命性脑脊髓病的背景下。由于线粒体三磷酸腺苷生成减少导致的神经元细胞自主性能量缺乏，是目前解释ETC紊乱中神经毒性的主要假说。为了明确ETC紊乱中神经病理学的潜在机制，我们在果蝇中构建了最常见的ETC紊乱类型——复合体I缺乏症的模型。我们的模型重现了该疾病的重要临床特征，包括神经元丢失、线粒体肿大、运动功能障碍和早期死亡。通过细胞类型特异性基因敲低，我们发现神经元和神经胶质细胞都对疾病表型有影响，并且神经胶质细胞在神经元毒性的发展中发挥着关键的非细胞自主性作用。我们的研究结果开辟了一条意想不到的研究途径，并可能促成新治疗策略的开发。
