We have previously identified a shift from TNF-α-induced apoptosis to necroptosis that occurs under hyperglycemic conditions. This shift involves the downregulation or silencing of caspases and concurrent upregulation of necroptotic proteins leading to activation of the necrosome. In addition, under hyperglycemic conditions in vivo, this shift in cell death mechanisms exacerbates neonatal hypoxia-ischemia (HI) brain injury. Here, we identify two major factors that drive the hyperglycemic shift to necroptosis: (1) reactive oxygen species (ROS) and (2) receptor-interacting protein kinase 1 (RIP1). ROS, including mitochondrial superoxide, led to the oxidation of RIP1, as well as formation and activation of the necrosome. Concurrently, ROS mediate a decrease in the levels and activation of executioner caspases-3, -6, and -7. Importantly, hyperglycemia and mitochondrial ROS result in the oxidation of RIP1 and loss of executioner caspases prior to death receptor engagement by TNF-α. Moreover, RIP1 partially controlled levels of mitochondrial ROS in the context of hyperglycemia. As a result of its regulation of ROS, RIP1 also regulated necrosome activation and caspase loss. Mitochondrial ROS exacerbated neonatal HI-brain injury in hyperglycemic mice, as a result of the shift from apoptosis to necroptosis.

我们之前已经确定了在高血糖条件下发生的从 TNF-α 诱导的细胞凋亡到坏死性凋亡的转变。这种转变涉及半胱天冬酶的下调或沉默以及导致坏死体激活的坏死蛋白的同时上调。此外，在体内高血糖条件下，细胞死亡机制的这种转变加剧了新生儿缺氧缺血 (HI) 脑损伤。在这里，我们确定了导致高血糖转变为坏死性凋亡的两个主要因素：(1) 活性氧 (ROS) 和 (2) 受体相互作用蛋白激酶 1 (RIP1)。ROS，包括线粒体超氧化物，导致 RIP1 的氧化，以及坏死体的形成和激活。同时，ROS 介导刽子手 caspase-3、-6 和 -7 水平和激活的降低。重要的，高血糖和线粒体 ROS 在死亡受体被 TNF-α 结合之前导致 RIP1 的氧化和刽子手半胱天冬酶的丢失。此外，在高血糖的情况下，RIP1 部分控制了线粒体 ROS 的水平。由于其对 ROS 的调节，RIP1 还调节坏死体激活和半胱天冬酶丢失。由于从细胞凋亡转变为坏死性凋亡，线粒体 ROS 加剧了高血糖小鼠的新生儿 HI 脑损伤。