Department of Military and Emergency Medicine, Uniformed Services University, Bethesda, MD 20814, USA.
Department of Military and Emergency Medicine, Uniformed Services University, Bethesda, MD 20814, USA; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817, USA.
Neuroscience. 2021 Nov 10;476:12-20. doi: 10.1016/j.neuroscience.2021.09.010. Epub 2021 Sep 17.
The hypothalamus plays an essential role in regulating whole-body energy and temperature homeostasis when adapting to environmental changes. We previously reported that heat exposure causes mitochondrial dysfunction and apoptosis in mouse skeletal muscle, and pretreatment with astaxanthin (AST), an antioxidant, prevents this effect. How the hypothalamus responds to heat stress remains largely unexplored. In this study, we investigated the effects of heat exposure on hypothalamic mitochondria in mice with and without AST pretreatment. During heat exposure, both vehicle and AST-treated mice had a hyperthermic response though no significant differences in peak core body temperature were noted between the two groups. Heat exposure induced mitochondrial fission in the hypothalamus, as manifested by increased mitochondrial fragmentation and expression of both total and phosphorylated dynamin-related protein 1. In addition, transmission electron microscopy revealed damaged and degraded mitochondria in the hypothalamus of heat-exposed mice. Heat induced apoptosis and mitophagy were further confirmed by increased formation of reactive oxygen species, activation of caspase 3/7 and expression of LC3 proteins. Moreover, heat exposure increased the expression of PINK1 and Parkin in mouse hypothalamus. In contrast, pretreatment with AST reduced these effects. These results demonstrate that heat stress-induced hypothalamic apoptosis is associated with altered mitochondrial dynamics favoring fission and mitophagy. AST protects the hypothalamus against heat-induced injury by preserving redox homeostasis and mitochondrial integrity.
下丘脑在适应环境变化时对调节全身能量和体温稳态起着至关重要的作用。我们之前曾报道过，热暴露会导致小鼠骨骼肌中线粒体功能障碍和细胞凋亡，而抗氧化剂虾青素（AST）预处理可预防这种作用。下丘脑对热应激的反应如何在很大程度上仍未得到探索。在这项研究中，我们研究了热暴露对有和没有 AST 预处理的小鼠下丘脑线粒体的影响。在热暴露期间，尽管两组之间的核心体温峰值没有显著差异，但载体和 AST 处理的小鼠均表现出体温升高的反应。热暴露诱导下丘脑中线粒体分裂，表现为线粒体片段化增加以及总和磷酸化动力相关蛋白 1 的表达增加。此外，透射电子显微镜显示热暴露小鼠下丘脑的线粒体受损和降解。活性氧的形成增加、半胱氨酸天冬氨酸蛋白酶 3/7 的激活和 LC3 蛋白的表达进一步证实了热诱导的细胞凋亡和线粒体自噬。此外，热暴露增加了小鼠下丘脑 PINK1 和 Parkin 的表达。相比之下，AST 预处理降低了这些作用。这些结果表明，热应激诱导的下丘脑细胞凋亡与改变的线粒体动力学有利于分裂和线粒体自噬有关。AST 通过维持氧化还原平衡和线粒体完整性来保护下丘脑免受热诱导的损伤。
