Protective Effects of Hif2 Inhibitor PT-2385 on a Neurological Disorder Induced by Deficiency of Irp2.
Protective Effects of Hif2 Inhibitor PT-2385 on a Neurological Disorder Induced by Deficiency of Irp2.
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Hif2 抑制剂 PT-2385 对 Irp2 缺陷引起的神经系统疾病的保护作用
DOI：
10.3389/fnins.2021.715222
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发表时间：
2021
影响因子：
4.3
通讯作者：
Li K
中科院分区：
文献类型：
--
作者：
Shen J;Xu L;Li Y;Dong W;Cai J;Liu Y;Zhao H;Xu T;Holtz EM;Chang Y;Qiao T;Li K
铁调节蛋白2（IRP 2）缺乏在小鼠和人类中引起小细胞性贫血和神经变性，由于功能性细胞铁耗竭。我们之前的体外研究数据表明，Irp 2缺失上调缺氧诱导因子亚基Hif 1 α和Hif 2 α的表达;抑制Hif 2 α可挽救Irp 2消融诱导的线粒体功能障碍;抑制Hif 1 α可抑制活性有氧糖酵解产生的过量乳酸。我们想知道Hif 1 α和Hif 2 α是否也在体内升高，并在Irp 2-/-小鼠的神经系统疾病中发挥类似的作用。在这项研究中，我们证实了在组织中，特别是在中枢神经系统中，包括Irp 2-/-小鼠主要受影响的小脑和脊髓中，Hif 2 α而不是Hif 1 α的上调。与这一观察结果一致，PT-2385抑制Hif 2 α，而不是PX-478抑制Hif 1 α，防止了神经退行性症状，这通过浦肯野细胞排列从收缩和不规则到完整和规则排列得到证明。PT-2385处理不仅在体内调节线粒体形态和质量，而且抑制糖酵解。因此，从糖酵解到氧化磷酸化（OXPHOS）的能量代谢的转变被逆转。我们的研究结果表明，Irp 2缺失诱导的Hif 2 α在体内负责OXPHOS和糖酵解之间的转换，这表明，据我们所知，Hif 2 α首次成为治疗IRP 2缺陷诱导的神经退行性综合征的临床潜在靶点。
Iron regulatory protein 2 (IRP2) deficiency in mice and humans causes microcytic anemia and neurodegeneration due to functional cellular iron depletion. Our previous in vitro 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 in vivo and play a similar role in neurological disorder of Irp2–/– 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 Irp2–/– 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 in vivo 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 vivo, 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.
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影响因子：
29
作者：
Anderson SA;Nizzi CP;Chang YI;Deck KM;Schmidt PJ;Galy B;Damnernsawad A;Broman AT;Kendziorski C;Hentze MW;Fleming MD;Zhang J;Eisenstein RS
通讯作者：
Eisenstein RS
影响因子：
64.8
作者：
Mancias, Joseph D.;Wang, Xiaoxu;Gygi, Steven P.;Harper, J. Wade;Kimmelman, Alec C.
通讯作者：
Kimmelman, Alec C.
影响因子：
20.3
作者：
Galy, B;Ferring, D;Hentze, MW
通讯作者：
Hentze, MW
影响因子：
29
作者：
Ghosh MC;Zhang DL;Jeong SY;Kovtunovych G;Ollivierre-Wilson H;Noguchi A;Tu T;Senecal T;Robinson G;Crooks DR;Tong WH;Ramaswamy K;Singh A;Graham BB;Tuder RM;Yu ZX;Eckhaus M;Lee J;Springer DA;Rouault TA
通讯作者：
Rouault TA
影响因子：
29
作者：
Chan SY;Zhang YY;Hemann C;Mahoney CE;Zweier JL;Loscalzo J
通讯作者：
Loscalzo J