Suhail Hamid, Nematullah Mohammad, Rashid Faraz, Sajad Mir, Fatma Mena, Singh Jaspreet, Zahoor Insha, Cheung Wing Lee, Tiwari Nivedita, Ayasolla Kameshwar, Kumar Ashok, Hoda Nasrul, Rattan Ramandeep, Giri Shailendra
Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA.
Department of Ophthalmology/Kresge Eye Institute, Department of Anatomy and Cell Biology, Department of Immunology and Microbiology, Wayne State University, Detroit, MI, USA.
iScience. 2023 Sep 15;26(10):107921. doi: 10.1016/j.isci.2023.107921. eCollection 2023 Oct 20.
Metabolism and energy processes governing oligodendrocyte function during neuroinflammatory disease are of great interest. However, how varied cellular environments affect oligodendrocyte activity during neuroinflammation is unknown. We demonstrate that activated microglial energy metabolism controls oligodendrocyte mitochondrial respiration and activity. Lipopolysaccharide/interferon gamma promote glycolysis and decrease mitochondrial respiration and myelin protein synthesis in rat brain glial cells. Enriched microglia showed an early burst in glycolysis. In microglia-conditioned medium, oligodendrocytes did not respire and expressed less myelin. SCENITH revealed metabolic derangement in microglia and O4-positive oligodendrocytes in endotoxemia and experimental autoimmune encephalitogenic models. The early burst of glycolysis in microglia was mediated by PDPK1 and protein kinase B/AKT signaling. We found that microglia-produced NO and itaconate, a tricarboxylic acid bifurcated metabolite, reduced mitochondrial respiration in oligodendrocytes. During inflammation, we discovered a signaling pathway in microglia that could be used as a therapeutic target to restore mitochondrial function in oligodendrocytes and induce remyelination.
神经炎症性疾病期间，少突胶质细胞功能的代谢和能量过程备受关注。然而，在神经炎症期间，不同的细胞环境如何影响少突胶质细胞的活性尚不清楚。我们证明，活化的小胶质细胞能量代谢控制少突胶质细胞的线粒体呼吸和活性。脂多糖/干扰素γ促进大鼠脑胶质细胞的糖酵解，降低线粒体呼吸和髓鞘蛋白合成。富集的小胶质细胞显示糖酵解早期爆发。在小胶质细胞条件培养基中，少突胶质细胞不进行呼吸，且髓鞘表达减少。SCENITH显示内毒素血症和实验性自身免疫性脑脊髓炎模型中小胶质细胞和O4阳性少突胶质细胞存在代谢紊乱。小胶质细胞中糖酵解的早期爆发由PDPK1和蛋白激酶B/AKT信号介导。我们发现小胶质细胞产生的一氧化氮和三羧酸分叉代谢产物衣康酸可降低少突胶质细胞的线粒体呼吸。在炎症期间，我们在小胶质细胞中发现了一条信号通路，可作为恢复少突胶质细胞线粒体功能和诱导髓鞘再生的治疗靶点。
