Asymmetrically Segregated Mitochondria Provide Cellular Memory of Hematopoietic Stem Cell Replicative History and Drive HSC Attrition
Asymmetrically Segregated Mitochondria Provide Cellular Memory of Hematopoietic Stem Cell Replicative History and Drive HSC Attrition
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DOI：
10.1016/j.stem.2020.01.016
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发表时间：
2020-03-05
期刊：
影响因子：
23.9
通讯作者：
Filippi, Marie-Dominique
中科院分区：
文献类型：
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作者：
Hinge, Ashwini;He, Jingyi;Filippi, Marie-Dominique
造血干细胞(HSCs)的代谢需求随其细胞周期活动而变化。然而，线粒体的潜在作用仍然不明确。我们发现，在复制激活线粒体后，HSC不可逆转地重塑线粒体网络，并且该网络在HSC重新进入静止状态后不会修复，这与造血祖细胞相反。HSCs在分裂活跃的过程中，通过不对称分离来保持和积累功能障碍的线粒体。从机制上讲，应激后线粒体聚集和去极化是由于线粒体分裂调节因子Drp1对线粒体失去活性所致。遗传学和药理学研究表明，在保持HSC静止的同时，DRp1的失活会导致HSC再生能力的丧失。在分子上，携带功能障碍的线粒体的HSCs可以重新进入静止状态，但在随后的分裂中无法同步核心细胞周期和代谢成分的转录控制。因此，线粒体形态和分离的保真度的丧失是HSC分区记忆的一种类型，并驱动HSC的磨损。
The metabolic requirements of hematopoietic stem cells (HSCs) change with their cell cycle activity. However, the underlying role of mitochondria remains ill-defined. Here we found that, after mitochondrial activation with replication, HSCs irreversibly remodel the mitochondrial network and that this network is not repaired after HSC re-entry into quiescence, contrary to hematopoietic progenitors. HSCs keep and accumulate dysfunctional mitochondria through asymmetric segregation during active division. Mechanistically, mitochondria aggregate and depolarize after stress because of loss of activity of the mitochondrial fission regulator Drp1 onto mitochondria. Genetic and pharmacological studies indicate that inactivation of Drp1 causes loss of HSC regenerative potential while maintaining HSC quiescence. Molecularly, HSCs carrying dysfunctional mitochondria can re-enter quiescence but fail to synchronize the transcriptional control of core cell cycle and metabolic components in subsequent division. Thus, loss of fidelity of mitochondrial morphology and segregation is one type of HSC divisional memory and drives HSC attrition.