期刊
CELL STEM CELL
卷 29, 期 9, 页码 1315-+出版社
CELL PRESS
DOI: 10.1016/j.stem.2022.07.010
关键词
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资金
- Canada Research Chair (CRC)
- CIHR
- Stem Cell Network
- NSERC-CGSM
Physiological changes in mitochondrial shape play a crucial role in regulating the quiescent state and activation potential of adult stem cells. Mitochondrial fragmentation promotes the exit from deep quiescence, while loss of the mitochondrial fusion protein OPA1 leads to premature activation and depletion of stem cells.
Quiescence regulation is essential for adult stem cell maintenance and sustained regeneration. Our studies uncovered that physiological changes in mitochondrial shape regulate the quiescent state of adult muscle stem cells (MuSCs). We show that MuSC mitochondria rapidly fragment upon an activation stimulus, via sys-temic HGF/mTOR, to drive the exit from deep quiescence. Deletion of the mitochondrial fusion protein OPA1 and mitochondrial fragmentation transitions MuSCs into G-alert quiescence, causing premature activation and depletion upon a stimulus. OPA1 loss activates a glutathione (GSH)-redox signaling pathway promoting cell-cycle progression, myogenic gene expression, and commitment. MuSCs with chronic OPA1 loss, lead-ing to mitochondrial dysfunction, continue to reside in G-alert but acquire severe cell-cycle defects. Addition-ally, we provide evidence that OPA1 decline and impaired mitochondrial dynamics contribute to age-related MuSC dysfunction. These findings reveal a fundamental role for OPA1 and mitochondrial dynamics in estab-lishing the quiescent state and activation potential of adult stem cells.
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