Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
J Cereb Blood Flow Metab. 2021 Jul;41(7):1523-1535. doi: 10.1177/0271678X20969588. Epub 2020 Nov 5.
Mitochondria may be transferred from cell to cell in the central nervous system and this process may help defend neurons against injury and disease. But how mitochondria maintain their functionality during the process of release into extracellular space remains unknown. Here, we report that mitochondrial protein O-GlcNAcylation is a critical process to support extracellular mitochondrial functionality. Activation of CD38-cADPR signaling in astrocytes robustly induced protein O-GlcNAcylation in mitochondria, while oxygen-glucose deprivation and reoxygenation showed transient and mild protein modification. Blocking the endoplasmic reticulum - Golgi trafficking with Brefeldin A or slc35B4 siRNA reduced O-GlcNAcylation, and resulted in the secretion of mitochondria with decreased membrane potential and mtDNA. Finally, loss-of-function studies verified that O-GlcNAc-modified mitochondria demonstrated higher levels of neuroprotection after astrocyte-to-neuron mitochondrial transfer. Collectively, these findings suggest that post-translational modification by O-GlcNAc may be required for supporting the functionality and neuroprotective properties of mitochondria released from astrocytes.
线粒体可能在中枢神经系统中从一个细胞转移到另一个细胞，这一过程有助于保护神经元免受损伤和疾病的影响。但是，线粒体在释放到细胞外间隙的过程中如何保持其功能仍不清楚。在这里，我们报告说线粒体蛋白 O-GlcNAc 化是支持细胞外线粒体功能的关键过程。星形胶质细胞中 CD38-cADPR 信号的激活强烈诱导了线粒体中的蛋白 O-GlcNAc 化，而氧葡萄糖剥夺和再氧合则显示出短暂和温和的蛋白修饰。用布雷菲德菌素 A 或 slc35B4 siRNA 阻断内质网-高尔基体运输，降低了 O-GlcNAc 化水平，导致线粒体膜电位和 mtDNA 降低的分泌。最后，功能丧失研究证实，O-GlcNAc 修饰的线粒体在星形胶质细胞到神经元线粒体转移后表现出更高水平的神经保护作用。总之，这些发现表明，O-GlcNAc 的翻译后修饰可能是支持从星形胶质细胞释放的线粒体的功能和神经保护特性所必需的。
