Department of Neurology, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China.
Department of Neurology, The Second People's Hospital of Hunan Province, Changsha 410007, Hunan, China.
Aging (Albany NY). 2021 Feb 19;13(4):6194-6204. doi: 10.18632/aging.202629.
Cerebral ischemia-reperfusion induces mitochondrial fragmentation and dysfunction, which plays a critical role in the subsequent neuronal death and neurological impairment. Protection of mitochondria is an effective strategy to prevent neuronal damage after cerebral ischemia-reperfusion injury. USP30 is a deubiquitinating enzyme that localizes to the outer mitochondrial membrane. USP30 participates in the regulation of mitophagy and maintenance of mitochondrial morphology. In this study, the neuroprotective effect of USP30 and the underlying mechanisms were assessed in an ischemia-reperfusion injury model. SK-N-BE (2) cells were subjected to oxygen-glucose deprivation/reperfusion (OGDR) insult. Ubiquitination of mitochondrial proteins is increased during the early stage of reperfusion after oxygen-glucose deprivation (OGD), but the ubiquitination of cytoplasmic proteins exhibits no obvious changes. OGDR insult also induces rapid ubiquitination and degradation of the mitochondrial fusion protein mitofusin 2 (MFN2) in the early stage of reperfusion after OGD. Overexpression of MFN2 attenuates OGDR induced mitochondrial fragmentation. USP30 overexpression suppresses OGDR-induced ubiquitination and degradation of MFN2, and protects against mitochondrial fragmentation. Therefore, precisely targeting USP30 may provide a novel therapeutic strategy for cerebral ischemia-reperfusion related disorders.
脑缺血再灌注诱导线粒体碎片化和功能障碍，在随后的神经元死亡和神经损伤中起着关键作用。保护线粒体是预防脑缺血再灌注损伤后神经元损伤的有效策略。USP30 是一种定位于外线粒体膜的去泛素化酶。USP30 参与调节自噬和维持线粒体形态。在这项研究中，在缺血再灌注损伤模型中评估了 USP30 的神经保护作用及其潜在机制。SK-N-BE（2）细胞受到氧葡萄糖剥夺/再灌注（OGDR）损伤。氧葡萄糖剥夺（OGD）后再灌注的早期，线粒体蛋白的泛素化增加，但细胞质蛋白的泛素化没有明显变化。OGDR 损伤也在 OGD 后再灌注的早期诱导线粒体融合蛋白线粒体融合蛋白 2（MFN2）的快速泛素化和降解。MFN2 的过表达减轻 OGDR 诱导的线粒体碎片化。USP30 的过表达抑制 OGDR 诱导的 MFN2 泛素化和降解，并防止线粒体碎片化。因此，精确靶向 USP30 可能为脑缺血再灌注相关疾病提供一种新的治疗策略。
