Oettinghaus B, Schulz J M, Restelli L M, Licci M, Savoia C, Schmidt A, Schmitt K, Grimm A, Morè L, Hench J, Tolnay M, Eckert A, D'Adamo P, Franken P, Ishihara N, Mihara K, Bischofberger J, Scorrano L, Frank S
Division of Neuropathology, Institute of Pathology, University Hospital Basel, Basel 4031, Switzerland.
Division of Neurophysiology, Institute of Physiology, Department of Biomedicine, University of Basel, Basel 4056, Switzerland.
Cell Death Differ. 2016 Jan;23(1):18-28. doi: 10.1038/cdd.2015.39. Epub 2015 Apr 24.
Well-balanced mitochondrial fission and fusion processes are essential for nervous system development. Loss of function of the main mitochondrial fission mediator, dynamin-related protein 1 (Drp1), is lethal early during embryonic development or around birth, but the role of mitochondrial fission in adult neurons remains unclear. Here we show that inducible Drp1 ablation in neurons of the adult mouse forebrain results in progressive, neuronal subtype-specific alterations of mitochondrial morphology in the hippocampus that are marginally responsive to antioxidant treatment. Furthermore, DRP1 loss affects synaptic transmission and memory function. Although these changes culminate in hippocampal atrophy, they are not sufficient to cause neuronal cell death within 10 weeks of genetic Drp1 ablation. Collectively, our in vivo observations clarify the role of mitochondrial fission in neurons, demonstrating that Drp1 ablation in adult forebrain neurons compromises critical neuronal functions without causing overt neurodegeneration.
平衡良好的线粒体分裂和融合过程对神经系统发育至关重要。主要的线粒体分裂调节因子动力相关蛋白1（Drp1）功能丧失在胚胎发育早期或出生前后是致命的，但线粒体分裂在成年神经元中的作用仍不清楚。在这里，我们表明，成年小鼠前脑神经元中可诱导的Drp1缺失会导致海马体中线粒体形态逐渐发生神经元亚型特异性改变，而这种改变对抗氧化治疗的反应微弱。此外，DRP1缺失会影响突触传递和记忆功能。尽管这些变化最终导致海马体萎缩，但在基因敲除Drp1后的10周内，它们不足以导致神经元细胞死亡。总的来说，我们的体内观察结果阐明了线粒体分裂在神经元中的作用，表明成年前脑神经元中Drp1的缺失会损害关键的神经元功能，而不会导致明显的神经退行性变。
