Späte Erik, Zhou Baoyu, Sun Ting, Kusch Kathrin, Asadollahi Ebrahim, Siems Sophie B, Depp Constanze, Werner Hauke B, Saher Gesine, Hirrlinger Johannes, Möbius Wiebke, Nave Klaus-Armin, Goebbels Sandra
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
Laboratory of Molecular Neurobiology, Department of Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Glia. 2024 Aug;72(8):1374-1391. doi: 10.1002/glia.24533. Epub 2024 Apr 8.
Oligodendrocytes and astrocytes are metabolically coupled to neuronal compartments. Pyruvate and lactate can shuttle between glial cells and axons via monocarboxylate transporters. However, lactate can only be synthesized or used in metabolic reactions with the help of lactate dehydrogenase (LDH), a tetramer of LDHA and LDHB subunits in varying compositions. Here we show that mice with a cell type-specific disruption of both Ldha and Ldhb genes in oligodendrocytes lack a pathological phenotype that would be indicative of oligodendroglial dysfunctions or lack of axonal metabolic support. Indeed, when combining immunohistochemical, electron microscopical, and in situ hybridization analyses in adult mice, we found that the vast majority of mature oligodendrocytes lack detectable expression of LDH. Even in neurodegenerative disease models and in mice under metabolic stress LDH was not increased. In contrast, at early development and in the remyelinating brain, LDHA was readily detectable in immature oligodendrocytes. Interestingly, by immunoelectron microscopy LDHA was particularly enriched at gap junctions formed between adjacent astrocytes and at junctions between astrocytes and oligodendrocytes. Our data suggest that oligodendrocytes metabolize lactate during development and remyelination. In contrast, for metabolic support of axons mature oligodendrocytes may export their own glycolysis products as pyruvate rather than lactate. Lacking LDH, these oligodendrocytes can also "funnel" lactate through their "myelinic" channels between gap junction-coupled astrocytes and axons without metabolizing it. We suggest a working model, in which the unequal cellular distribution of LDH in white matter tracts facilitates a rapid and efficient transport of glycolysis products among glial and axonal compartments.
少突胶质细胞和星形胶质细胞在代谢上与神经元区室相互耦合。丙酮酸和乳酸可以通过单羧酸转运体在胶质细胞和轴突之间穿梭。然而，乳酸只能在乳酸脱氢酶（LDH）的帮助下合成或用于代谢反应，LDH是由不同组成的LDHA和LDHB亚基组成的四聚体。在这里，我们表明，少突胶质细胞中Ldha和Ldhb基因发生细胞类型特异性破坏的小鼠缺乏指示少突胶质细胞功能障碍或轴突代谢支持不足的病理表型。事实上，在对成年小鼠进行免疫组织化学、电子显微镜和原位杂交分析后，我们发现绝大多数成熟少突胶质细胞缺乏可检测到的LDH表达。即使在神经退行性疾病模型和处于代谢应激状态的小鼠中，LDH也没有增加。相反，在早期发育和正在进行髓鞘再生的大脑中，未成熟少突胶质细胞中很容易检测到LDHA。有趣的是，通过免疫电子显微镜观察，LDHA特别富集在相邻星形胶质细胞之间形成的缝隙连接处以及星形胶质细胞与少突胶质细胞之间的连接处。我们的数据表明，少突胶质细胞在发育和髓鞘再生过程中代谢乳酸。相比之下，为了给轴突提供代谢支持，成熟少突胶质细胞可能会将自身的糖酵解产物以丙酮酸而非乳酸的形式输出。由于缺乏LDH，这些少突胶质细胞也可以通过其在缝隙连接耦合的星形胶质细胞和轴突之间的“髓鞘”通道“输送”乳酸而不进行代谢。我们提出了一个工作模型，其中白质束中LDH的不均匀细胞分布促进了糖酵解产物在胶质细胞和轴突区室之间的快速有效运输。
