Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada.
Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada; Department of Pharmacology & Therapeutics, University of Manitoba, Winnipeg, MB, Canada.
Mitochondrion. 2021 Mar;57:63-75. doi: 10.1016/j.mito.2020.12.008. Epub 2020 Dec 27.
Hyperammonemia is very toxic to the brain, leading to inflammation, disruption of brain cellular energy metabolism and cognitive function. However, the underlying mechanism(s) for these impairments is still not fully understood. This study investigated the effects of ammonia in hippocampal astroglia derived from C57BL/6 mice. Parameters measured included oxygen consumption rates (OCR), ATP, cytochrome c oxidase (COX) activity, alterations in oxidative phosphorylation (OXPHOS), nuclear factor kappa B (NF-κB) subunits, key regulators of mitochondrial biogenesis (peroxisome proliferator-activated receptor gamma coactivator1-alpha (PGC-1α), calcium/calmodulin-dependent protein kinase II (CaMKII), cAMP-response element binding protein (CREB), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), early growth response (Egr) factor family of proteins, and mitochondrial transcription factor A (TFAM). Ammonia was found to decrease mitochondrial numbers, potentially through a CaMKII-CREB-PGC1α-Nrf2 pathway in astroglia. Ammonia did not alter the levels of Egrs and TFAM in astroglia. Ammonia decreased OCR, ATP, COX, and OXPHOS levels in astroglia. To assess whether energy metabolism is reduced by ammonia through NF-κB associated pathways, astroglia were treated with ammonia alone or with NF-κB inhibitors such as Bay11-7082 or SN50. Mitochondrial OCR levels were reduced in the presence of NF-κB inhibitors; however co-treatment of NF-κB inhibitors and ammonia reversed mitochondrial deficits. Further, ammonia increased translocation of the NF-κB p65 into the nucleus of astroglia that correlates with an increased activity of NF-κB. These findings suggest that the NF-κB signaling pathway is putatively involved in ammonia-induced changes in bioenergetics in astroglia. Such research has critical implications for the treatment of disorders in which brain bioenergetics is compromised.
高氨血症对大脑非常有毒，导致炎症、大脑细胞能量代谢和认知功能障碍。然而，这些损伤的潜在机制尚不完全清楚。本研究探讨了氨对 C57BL/6 小鼠海马星形胶质细胞的影响。测量的参数包括耗氧量 (OCR)、ATP、细胞色素 c 氧化酶 (COX) 活性、氧化磷酸化 (OXPHOS) 的改变、核因子 kappa B (NF-κB) 亚单位、线粒体生物发生的关键调节剂（过氧化物酶体增殖物激活受体 γ共激活因子 1-α (PGC-1α)、钙/钙调蛋白依赖性蛋白激酶 II (CaMKII)、cAMP 反应元件结合蛋白 (CREB)、核因子 (红细胞衍生 2)-样 2 (Nrf2)、早期生长反应 (Egr) 因子家族蛋白和线粒体转录因子 A (TFAM)。研究发现，氨通过星形胶质细胞中的 CaMKII-CREB-PGC1α-Nrf2 途径减少线粒体数量。氨不会改变星形胶质细胞中 Egrs 和 TFAM 的水平。氨降低了星形胶质细胞中的 OCR、ATP、COX 和 OXPHOS 水平。为了评估能量代谢是否通过 NF-κB 相关途径被氨降低，星形胶质细胞单独用氨或 NF-κB 抑制剂（如 Bay11-7082 或 SN50）处理。NF-κB 抑制剂存在时，线粒体 OCR 水平降低；然而，NF-κB 抑制剂和氨的共同处理逆转了线粒体缺陷。此外，氨增加了 NF-κB p65 向星形胶质细胞核内的易位，这与 NF-κB 活性的增加相关。这些发现表明，NF-κB 信号通路可能参与了氨诱导的星形胶质细胞中生物能学变化。这种研究对于治疗脑生物能学受损的疾病具有重要意义。
