Shen Jiaqi, Xu Li, Li Yuxuan, Dong Weichen, Cai Jing, Liu Yutong, Zhao Hongting, Xu Tianze, Holtz Esther Meyron, Chang Yanzhong, Qiao Tong, Li Kuanyu
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China.
Department of Neurology, The Affiliated Jinling Hospital of Nanjing University Medical School, Nanjing, China.
Front Neurosci. 2021 Oct 5;15:715222. doi: 10.3389/fnins.2021.715222. eCollection 2021.
Iron regulatory protein 2 (IRP2) deficiency in mice and humans causes microcytic anemia and neurodegeneration due to functional cellular iron depletion. Our previous data have demonstrated that Irp2 depletion upregulates hypoxia-inducible factor subunits Hif1α and Hif2α expression; inhibition of Hif2α rescues Irp2 ablation-induced mitochondrial dysfunction; and inhibition of Hif1α suppresses the overdose production of lactic acid derived from actively aerobic glycolysis. We wonder whether Hif1α and Hif2α are also elevated and play a similar role in neurological disorder of mice. In this study, we confirmed the upregulation of Hif2α, not Hif1α, in tissues, particularly in the central nervous system including the mainly affected cerebellum and spinal cord of mice. Consistent with this observation, inhibition of Hif2α by PT-2385, not Hif1α by PX-478, prevented neurodegenerative symptoms, which were proved by Purkinje cell arrangement from the shrunken and irregular to the full and regular array. PT-2385 treatment did not only modulate mitochondrial morphology and quality but also suppressed glycolysis. Consequently, the shift of energy metabolism from glycolysis to oxidative phosphorylation (OXPHOS) was reversed. Our results indicate that Irp2 depletion-induced Hif2α is, , in charge of the switch between OXPHOS and glycolysis, suggesting that, for the first time to our knowledge, Hif2α is a clinically potential target in the treatment of IRP2 deficiency-induced neurodegenerative syndrome.
小鼠和人类体内的铁调节蛋白2（IRP2）缺乏会导致小细胞性贫血和神经退行性变，这是由于细胞功能性缺铁所致。我们之前的数据表明，Irp2缺失会上调缺氧诱导因子亚基Hif1α和Hif2α的表达；抑制Hif2α可挽救Irp2缺失诱导的线粒体功能障碍；抑制Hif1α可抑制活跃有氧糖酵解产生的过量乳酸。我们想知道Hif1α和Hif2α在小鼠神经疾病中是否也会升高并发挥类似作用。在本研究中，我们证实了在小鼠组织中，尤其是在包括主要受影响的小脑和脊髓在内的中枢神经系统中，Hif2α而非Hif1α上调。与这一观察结果一致，PT - 2385抑制Hif2α而非PX - 478抑制Hif1α可预防神经退行性症状，这通过浦肯野细胞排列从萎缩和不规则变为完整和规则得以证明。PT - 2385处理不仅调节了线粒体形态和质量，还抑制了糖酵解。因此，能量代谢从糖酵解向氧化磷酸化（OXPHOS）的转变得以逆转。我们的结果表明，Irp2缺失诱导的Hif2α负责OXPHOS和糖酵解之间的转换，这表明据我们所知，Hif2α首次成为治疗IRP2缺乏诱导的神经退行性综合征的潜在临床靶点。
