Pearson syndrome-like anemia induced by accumulation of mutant mtDNA and anemia with imbalanced white blood cell lineages induced by Drp1 deletion in a murine model
Pearson syndrome-like anemia induced by accumulation of mutant mtDNA and anemia with imbalanced white blood cell lineages induced by Drp1 deletion in a murine model
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小鼠模型中突变 mtDNA 积累诱导的皮尔逊综合征样贫血和 Drp1 缺失诱导的白细胞谱系失衡贫血
DOI：
10.1016/j.phrs.2022.106467
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发表时间：
2022
影响因子：
9.3
通讯作者：
Nakada Kazuto
中科院分区：
文献类型：
--
作者：
Ishikawa Kaori;Honma Yo;Yoshimi Ayami;Katada Shun;Ishihara Takaya;Ishihara Naotada;Nakada Kazuto
线粒体呼吸和形态的调节对于维持稳态造血是重要的，然而很少有研究比较评估异常线粒体呼吸和动力学单独或组合对血细胞分化的影响。本研究试图在具有以下一种或两种缺陷的小鼠模型中探索这些效应：线粒体DNA（ΔmtDNA）的大规模缺失，积累到不同程度，或线粒体裂变因子Drp1的敲除。发现每种缺陷都独立地引起贫血，但表现明显不同。前者表现出异常呼吸的迹象，类似于皮尔逊综合征，而后者表现出异常线粒体动力学的迹象，并与白细胞谱系的相对比例的变化有关。结合这些缺陷的作用，扩大异常铁代谢红细胞生成，加重贫血的累加方式。我们的研究结果表明，线粒体呼吸和动力学在造血分化的不同过程和细胞谱系中发挥着不同的作用。
Regulation of mitochondrial respiration and morphology is important for maintaining steady-state hematopoiesis, yet few studies have comparatively evaluated the effects of abnormal mitochondrial respiration and dynamics on blood-cell differentiation in isolation or combination. This study sought to explore these effects in mouse models with one or both of the following deficits: a large-scale deletion of mitochondrial DNA (ΔmtDNA), accumulated to varying extents, or knockout of the mitochondrial fission factor Drp1. Each deficit was found to independently provoke anemia but with clearly different manifestations. The former showed signs of aberrant respiration, analogous to Pearson syndrome, while the latter showed signs of abnormal mitochondrial dynamics and was associated with changes in the relative proportions of leukocyte lineages. Combining these deficits acted to amplify abnormal iron metabolism in erythropoiesis, exacerbating anemia in an additive manner. Our results indicate that mitochondrial respiration and dynamics play distinct roles in different sets of processes and cell lineages in hematopoietic differentiation.