https://ror.org/040af2s02 Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
https://ror.org/040af2s02 Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Life Sci Alliance. 2023 Sep 1;6(11). doi: 10.26508/lsa.202302036. Print 2023 Nov.
Energetic insufficiency, excess production of reactive oxygen species (ROS), and aberrant signaling partially account for the diverse pathology of mitochondrial diseases. Whether interventions affecting ROS, a regulator of stem cell pools, could modify somatic stem cell homeostasis remains unknown. Previous data from mitochondrial DNA mutator mice showed that increased ROS leads to oxidative damage in erythroid progenitors, causing lifespan-limiting anemia. Also unclear is how ROS-targeted interventions affect terminally differentiated tissues. Here, we set out to test in mitochondrial DNA mutator mice how ubiquitous expression of the alternative oxidase (AOX), which attenuates ROS production, affects murine stem cell pools. We found that AOX does not affect neural stem cells but delays the progression of mutator-driven anemia. Furthermore, when combined with the mutator, AOX potentiates mitochondrial stress and inflammatory responses in skeletal muscle. These differential cell type-specific findings demonstrate that AOX expression is not a global panacea for curing mitochondrial dysfunction. ROS attenuation must be carefully studied regarding specific underlying defects before AOX can be safely used in therapy.
能量不足、活性氧（ROS）过度产生和信号异常部分解释了线粒体疾病的多种病理。影响 ROS（一种干细胞池调节剂）的干预措施是否可以改变体干细胞的稳态尚不清楚。先前来自线粒体 DNA 突变体小鼠的研究数据表明，ROS 增加会导致红系祖细胞的氧化损伤，从而导致寿命受限的贫血。目前尚不清楚 ROS 靶向干预如何影响终末分化组织。在这里，我们着手测试线粒体 DNA 突变体小鼠中普遍表达的替代氧化酶（AOX），该酶可减轻 ROS 的产生，对小鼠干细胞池有何影响。我们发现 AOX 不影响神经干细胞，但会延迟突变驱动的贫血的进展。此外，当与突变体结合时，AOX 会加剧骨骼肌中的线粒体应激和炎症反应。这些细胞类型特异性差异发现表明，AOX 表达不是治疗线粒体功能障碍的通用万灵药。在安全地将 AOX 用于治疗之前，必须仔细研究 ROS 衰减与特定潜在缺陷的关系。
