Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 FOUR Future Veterinary Medicine Leading Education & Research Center, Seoul National University, Seoul, South Korea.
Autophagy. 2024 Jul;20(7):1505-1522. doi: 10.1080/15548627.2024.2323785. Epub 2024 Mar 6.
Damaged mitochondria accumulation in diabetes is one of the main features that contribute to increased incidence of cognitive impairment by inducing apoptosis. Butyrate is a major metabolite produced by microbiota that has neuroprotective effects by regulating mitochondrial function. However, detailed mechanisms underlying how butyrate can regulate neuronal mitophagy remain unclear. Here, we examined the regulatory effects of sodium butyrate (NaB) on high glucose-induced mitophagy dysregulation, neuronal apoptosis, and cognitive impairment and its underlying mechanisms in human-induced pluripotent stem cell-derived neurons, SH-SY5Ys, and streptozotocin (STZ)-induced diabetic mice. In our results, diabetic mice showed gut-microbiota dysbiosis, especially a decreased number of butyrate-producing bacteria and reduced NaB plasma concentration. NaB ameliorated high glucose-induced neuronal mitochondrial dysfunction by recovering PRKN/Parkin-mediated mitophagy. High glucose-induced reactive oxygen species (ROS) and -inhibited PRKAA/AMPKα stimulated the RELA/p65-HDAC8 complex, which downregulated PRKN protein expression by binding to the promoter region. NaB restored PRKN expression by blocking RELA nuclear translocation and directly inhibiting HDAC8 in the nucleus. In addition, HDAC8 overexpression inhibited the positive effect of NaB on high glucose-induced mitophagy dysfunction and neuronal apoptosis. Oral administration of NaB improved cognitive impairment in diabetic mice by restoring mitophagy in the hippocampus. Taken together, NaB ameliorates neuronal mitophagy through PRKN restoration by inhibiting RELA-HDAC8 complexes, suggesting that NaB is an important substance for protecting neuronal apoptosis in diabetes-associated cognitive impairment.
糖尿病中线粒体损伤的积累是导致认知功能障碍发生率增加的主要特征之一，它通过诱导细胞凋亡来实现。丁酸盐是微生物群产生的主要代谢物，通过调节线粒体功能具有神经保护作用。然而，丁酸盐如何调节神经元细胞自噬的详细机制尚不清楚。在这里，我们研究了丁酸钠（NaB）对高糖诱导的线粒体自噬失调、神经元细胞凋亡和认知障碍的调节作用及其在人诱导多能干细胞源性神经元（SH-SY5Y）和链脲佐菌素（STZ）诱导的糖尿病小鼠中的潜在机制。在我们的研究结果中，糖尿病小鼠表现出肠道微生物群失调，特别是产丁酸盐细菌的数量减少和血浆中 NaB 浓度降低。NaB 通过恢复 PRKN/Parkin 介导的自噬来改善高糖诱导的神经元线粒体功能障碍。高糖诱导的活性氧（ROS）和抑制的 PRKAA/AMPKα 刺激 RELA/p65-HDAC8 复合物，通过与启动子区域结合来下调 PRKN 蛋白表达。NaB 通过阻断 RELA 核转位和直接抑制核内的 HDAC8 来恢复 PRKN 表达。此外，HDAC8 的过表达抑制了 NaB 对高糖诱导的线粒体自噬功能障碍和神经元细胞凋亡的正向作用。口服 NaB 通过恢复海马体中的自噬来改善糖尿病小鼠的认知障碍。总之，NaB 通过抑制 RELA-HDAC8 复合物来改善神经元细胞自噬，提示 NaB 是保护糖尿病相关认知障碍中神经元细胞凋亡的重要物质。
