論文 - 詳細
| RRC ID | 88522 |
|---|---|
| 著者 | Zhang K, Zhao H, Sheng Y, Chen X, Xu P, Wang J, Ji Z, He Y, Gao WQ, Zhu HH. |
| タイトル | Zeb1 sustains hematopoietic stem cell functions by suppressing mitofusin-2-mediated mitochondrial fusion. |
| ジャーナル | Cell Death Dis |
| Abstract |
Metabolic status is essential in maintaining normal functions of hematopoietic stem cells (HSCs). However, how the dynamic of the mitochondrion, as a central organelle in metabolism, is molecularly regulated to orchestrate metabolism and HSC stemness remains to be elucidated. Here, we focus on the role of Zeb1, a well-characterized epithelial-to-mesenchymal transition (EMT) inducer which has been demonstrated to confer stem-cell-like characteristics in multiple cancer types in stemness regulation of HSCs. Using a Zeb1-tdTomato reporter mouse model, we find that Zeb1+Lin-Sca-1+c-Kit+ cells (Zeb1+-LSKs) represent a subset of functional long-term HSCs. Zeb1+LSKs exhibit a reduced reactive oxygen species (ROS) level, low mitochondrial mass, low mitochondrial membrane potential (MMP), and particularly small, round fragmented mitochondria. Of note, ectopic expression of Zeb1 leads to a fragmented mitochondrial morphology with a low mitochondrial metabolic status in EML cells. In addition, Zeb1-knockout (Zeb1-KO) LSKs from fetal liver display an exhausted stem-cell activity. Zeb1 deficiency results in elongated and tubulated mitochondria with increased mitochondrial mass, elevated MMP, and higher ROS production. Mechanistically, Zeb1 acts as a transcriptional suppressor on the key mitochondrial-fusion protein Mitofusin-2 (encoded by Mfn2). We highlight an important role of Zeb1 in the regulation of mitochondrial morphology in HSC and the metabolic control of HSC stemness by repressing Mfn2-mediated mitochondrial fusion. |
| 巻・号 | 13(8) |
| ページ | 735 |
| 公開日 | 2022-8-25 |
| DOI | 10.1038/s41419-022-05194-w |
| PII | 10.1038/s41419-022-05194-w |
| PMID | 36008379 |
| PMC | PMC9411618 |
| MeSH | Animals Epithelial-Mesenchymal Transition Hematopoietic Stem Cells* / metabolism Mice Mitochondria / metabolism Mitochondrial Dynamics* Reactive Oxygen Species / metabolism |
| IF | 6.304 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 実験動物マウス | RBRC01923 |