Deragon Matthew A, McCaig William D, Patel Payal S, Haluska Robert J, Hodges Alexa L, Sosunov Sergey A, Murphy Michael P, Ten Vadim S, LaRocca Timothy J
Department of Basic and Clinical Sciences, Albany College of Pharmacy and Health Sciences, Albany, NY, 12208, USA.
Department of Pediatrics, Columbia University, New York, NY, 10032, USA.
Cell Death Discov. 2020 Nov 26;6(1):132. doi: 10.1038/s41420-020-00370-3.
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，在高血糖条件下会发生从肿瘤坏死因子-α（TNF-α）诱导的凋亡向坏死性凋亡的转变。这种转变涉及半胱天冬酶的下调或沉默以及坏死性凋亡蛋白的同时上调，从而导致坏死小体的激活。此外，在体内高血糖条件下，这种细胞死亡机制的转变会加剧新生儿缺氧缺血（HI）脑损伤。在此，我们确定了驱动高血糖向坏死性凋亡转变的两个主要因素：（1）活性氧（ROS）和（2）受体相互作用蛋白激酶1（RIP1）。包括线粒体超氧化物在内的ROS导致RIP1氧化，以及坏死小体的形成和激活。同时，ROS介导了执行性半胱天冬酶-3、-6和-7的水平降低及激活减少。重要的是，在TNF-α与死亡受体结合之前，高血糖和线粒体ROS导致RIP1氧化以及执行性半胱天冬酶丧失。此外，在高血糖背景下，RIP1部分控制了线粒体ROS的水平。由于其对ROS的调节作用，RIP1还调节了坏死小体的激活和半胱天冬酶丧失。由于从凋亡向坏死性凋亡的转变，线粒体ROS加剧了高血糖小鼠的新生儿HI脑损伤。
