Graduate School of Fisheries and Environmental Sciences, Nagasaki University, Nagasaki 8528521, Japan.
Department of Pathology, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 8528523, Japan.
Mar Drugs. 2022 Oct 25;20(11):660. doi: 10.3390/md20110660.
Astaxanthin (AX) is a carotenoid that exerts potent antioxidant activity and acts in cell membranes and mitochondria, which consist of the bilayer molecules. Targeting mitochondria to ameliorate inflammatory diseases by regulating mitochondrial metabolism has become possible and topical. Although AX has been shown to have anti-inflammatory effects in various cells, the mechanisms are quite different. In particular, the role of AX on mitochondrial metabolism in macrophages is still unknown. In this study, we investigated the effect of AX on mitochondria-mediated inflammation and its mechanisms in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. AX attenuated the mitochondrial O production and maintained the mitochondrial membrane potential, implying that AX preserved mitochondrial homeostasis to avoid LPS stimulation-induced mitochondrial dysfunction. Additionally, AX prevented the decrease in mitochondrial complexes I, II, and III, which were caused by LPS stimulation. Especially, AX inhibited the reduction in mitochondrial succinate dehydrogenase (SDH; complex II) activity and upregulated the protein and mRNA level of SDH complex, subunit B. Furthermore, AX blocked the IL-1β expression by regulating the SDH-HIF-1α axis and suppressed the energy shift from an OXPHOS phenotype to a glycolysis phenotype. These findings revealed important effects of AX on mitochondrial enzymes as well as on mitochondrial energy metabolism in the immune response. In addition, these raised the possibility that AX plays an important role in other diseases caused by SDH mutation and metabolic disorders.
虾青素 (AX) 是一种类胡萝卜素，具有强大的抗氧化活性，作用于由双层分子组成的细胞膜和线粒体。通过调节线粒体代谢来靶向线粒体改善炎症性疾病已成为可能和热门话题。尽管 AX 已被证明在各种细胞中具有抗炎作用，但机制却大不相同。特别是，AX 对巨噬细胞中线粒体代谢的作用仍不清楚。在这项研究中，我们研究了 AX 对脂多糖 (LPS) 刺激的 RAW264.7 细胞中线粒体介导的炎症及其机制的影响。AX 减弱了线粒体 O 的产生并维持了线粒体膜电位，这意味着 AX 维持了线粒体的动态平衡，以避免 LPS 刺激引起的线粒体功能障碍。此外，AX 防止了 LPS 刺激引起的线粒体复合物 I、II 和 III 的减少。特别是，AX 抑制了线粒体琥珀酸脱氢酶 (SDH；复合物 II) 活性的降低，并上调了 SDH 复合物亚基 B 的蛋白和 mRNA 水平。此外，AX 通过调节 SDH-HIF-1α 轴阻断了 IL-1β 的表达，并抑制了从 OXPHOS 表型向糖酵解表型的能量转移。这些发现揭示了 AX 对线粒体酶以及免疫反应中线粒体能量代谢的重要影响。此外，这些发现提出了 AX 在由 SDH 突变和代谢紊乱引起的其他疾病中可能发挥重要作用的可能性。
