Kim Ji-Eun, Wang Su Hyeon, Kang Tae-Cheon
Department of Anatomy and Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon, Kangwon-do, 24252, South Korea.
Sci Rep. 2025 Jul 18;15(1):26077. doi: 10.1038/s41598-025-12214-0.
Astrocytes have specialized functions depending on their localization. This region-dependent heterogeneity of astrocytes shows marked difference in astroglial responses to various stimuli. In the hippocampus, the populations of astrocytes in the stratum radiatum of the CA1 region (CA1 astrocytes) and the molecular layer of the dentate gyrus (DG astrocytes) have more complex structures than other regions. In the present study, we investigated whether oxidative stress induces distinct regulation of mitochondrial dynamics in CA1- and DG astrocytes, and which signaling pathways are relevant to these region-specific events in male rats. L-Buthionine sulfoximine (BSO)-induced oxidative stress led to mitochondrial fission in DG astrocytes concomitant with increased leucine-rich repeat protein phosphatase 1 (PHLPP1) expression and dynamin-related protein 1 (DRP1) S616 phosphorylation without altering AKT S473 and glycogen synthase kinase 3β (GSK3β) S9 phosphorylation, which were inhibited by PHLPP1 siRNA and SC79 (an AKT activator). BSO increased AKT S473 and GSK3β S9 phosphorylation in CA1 astrocytes without affecting their mitochondrial length or PHLPP1 expression, which was attenuated by 3-chloroacetyl-indole (an AKT inhibitor). These findings suggest that PHLPP1 may facilitate mitochondrial fragmentation in response to oxidative stress through the AKT-GSK3β-DRP1 pathway in DG astrocytes, but not in CA1 astrocytes, highlighting the region-specific heterogeneity in astrocytes.
星形胶质细胞根据其定位具有特定功能。星形胶质细胞这种区域依赖性的异质性在对各种刺激的星形胶质反应中表现出显著差异。在海马体中，CA1区辐射层（CA1星形胶质细胞）和齿状回分子层（DG星形胶质细胞）中的星形胶质细胞群体比其他区域具有更复杂的结构。在本研究中，我们调查了氧化应激是否会在CA1和DG星形胶质细胞中诱导线粒体动力学的不同调节，以及哪些信号通路与雄性大鼠中这些区域特异性事件相关。L-丁硫氨酸亚砜胺（BSO）诱导的氧化应激导致DG星形胶质细胞中的线粒体分裂，同时富含亮氨酸重复蛋白磷酸酶1（PHLPP1）表达增加和动力蛋白相关蛋白1（DRP1）的S616磷酸化增加，而不改变AKT的S473和糖原合酶激酶3β（GSK3β）的S9磷酸化，这被PHLPP1小干扰RNA和SC79（一种AKT激活剂）所抑制。BSO增加了CA1星形胶质细胞中AKT的S473和GSK3β的S9磷酸化，但不影响其线粒体长度或PHLPP1表达，这被3-氯乙酰吲哚（一种AKT抑制剂）所减弱。这些发现表明，PHLPP1可能通过DG星形胶质细胞中的AKT-GSK3β-DRP1途径促进对氧化应激的线粒体碎片化，但在CA1星形胶质细胞中则不然，这突出了星形胶质细胞中区域特异性的异质性。
