Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Pediatric Research Institute, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, P.R China.
Cell Stem Cell. 2020 Mar 5;26(3):420-430.e6. doi: 10.1016/j.stem.2020.01.016. Epub 2020 Feb 13.
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.
造血干细胞（HSCs）的代谢需求会随着其细胞周期活动而改变。然而，线粒体的潜在作用仍未得到明确界定。在这里，我们发现，在复制后通过线粒体激活后，HSCs 会不可逆转地重塑线粒体网络，而这种网络在 HSC 重新进入静止期后不会被修复，这与造血祖细胞不同。在活跃分裂过程中，HSCs 通过不对称分离保留和积累功能失调的线粒体。从机制上讲，由于线粒体分裂调节剂 Drp1 失去活性而转移到线粒体上，线粒体在应激后聚集和去极化。遗传和药理学研究表明，失活 Drp1 会导致 HSC 再生潜能丧失，同时保持 HSC 静止。从分子上讲，携带功能失调线粒体的 HSCs 可以重新进入静止期，但无法在随后的分裂中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丧失是 HSC 分裂记忆的一种类型，并导致 HSC 耗竭。
