Leigh氏综合征小鼠模型可以通过干预使脑高氧恢复正常，但不能通过激活HIF来实现，这一成果由美国麻省总医院的Vamsi K. Mootha和Warren M. Zapol等研究人员合作取得。该研究论文发表在2019年10月刊的国际学术期刊《细胞—代谢》上。

研究人员发现四种不同方式的遗传性激活缺氧诱导因子转录程序均不足以挽救疾病。相反，研究人员观察到了随年龄变化的全身氧气消耗量下降。这些小鼠表现出脑组织高氧，可通过低氧呼吸使其正常化。减少氧气输送的替代实验方法，包括呼吸一氧化碳（空气中600 ppm）或严重贫血，可以逆转神经系统疾病。因此，未消耗的氧气是该疾病病理最可能的罪魁祸首。尽管低氧反应的药理激活不太可能缓解体内疾病，但安全地使脑组织高氧正常化的干预措施可能具有治疗潜力。

据介绍，Leigh氏综合征是一种破坏性的线粒体疾病，目前尚无经证实的疗法。研究人员之前的研究发现，慢性持续缺氧可以预防甚至逆转由复合物I缺失的Ndufs4基因敲除小鼠模型和Leigh氏综合征导致的神经系统疾病。

附：英文原文

Title: Leigh Syndrome Mouse Model Can Be Rescued by Interventions that Normalize Brain Hyperoxia, but Not HIF Activation

Author: Isha H. Jain, Luca Zazzeron, Olga Goldberger, Eizo Marutani, Gregory R. Wojtkiewicz, Tslil Ast, Hong Wang, Grigorij Schleifer, Anna Stepanova, Kathleen Brepoels, Luc Schoonjans, Peter Carmeliet, Alexander Galkin, Fumito Ichinose, Warren M. Zapol, Vamsi K. Mootha

Issue&Volume: VOLUME 30, ISSUE 4

Abstract: 

Leigh syndrome is a devastating mitochondrial disease for which there are no proven therapies. We previously showed that breathing chronic, continuous hypoxia can prevent and even reverse neurological disease in the Ndufs4 knockout (KO) mouse model of complex I (CI) deficiency and Leigh syndrome. Here, we show that genetic activation of the hypoxia-inducible factor transcriptional program via any of four different strategies is insufficient to rescue disease. Rather, we observe an age-dependent decline in whole-body oxygen consumption. These mice exhibit brain tissue hyperoxia, which is normalized by hypoxic breathing. Alternative experimental strategies to reduce oxygen delivery, including breathing carbon monoxide (600 ppm in air) or severe anemia, can reverse neurological disease. Therefore, unused oxygen is the most likely culprit in the pathology of this disease. While pharmacologic activation of the hypoxia response is unlikely to alleviate disease in vivo, interventions that safely normalize brain tissue hyperoxia may hold therapeutic potential.

DOI: 10.1016/j.cmet.2019.07.006

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30379-1