Somatic Progenitor Cell Vulnerability to Mitochondrial DNA Mutagenesis Underlies Progeroid Phenotypes in Polg Mutator Mice
Somatic Progenitor Cell Vulnerability to Mitochondrial DNA Mutagenesis Underlies Progeroid Phenotypes in Polg Mutator Mice
复制标题
DOI：
10.1016/j.cmet.2011.11.012
复制
发表时间：
2012-01-04
期刊：
影响因子：
29
通讯作者：
Suomalainen, Anu
中科院分区：
文献类型：
--
作者：
Ahlqvist, Kati J.;Hamalainen, Riikka H.;Suomalainen, Anu
体细胞干细胞（SSC）功能障碍在具有基因组DNA修复缺陷的不同早衰表型小鼠中是典型的。在具有Polg外切酶活性缺陷的小鼠中，MtDNA突变也通过一种未知的机制导致类早衰症状。我们发现Polg-Mutator小鼠在胚胎发生时就已经出现神经（NSC）和造血祖细胞（HPC）功能障碍。体外NSC自我更新减少，体内静态NSC数量减少。造血干细胞表现出异常的谱系分化，导致贫血和淋巴细胞减少。n -乙酰- l-半胱氨酸治疗可挽救NSC和HPC异常，表明mtDNA诱变诱导的细微ROS/氧化还原变化可调节SSC功能。我们的研究结果表明，mtDNA突变早期影响SSC功能，但表现为老年非分裂组织的呼吸链缺陷。有丝分裂后细胞中mtDNA缺失且无早衰的缺失小鼠具有正常的ssc。我们认为SSC对mtDNA突变敏感，SSC的线粒体功能障碍可能是早衰症状的基础。
Somatic stem cell (SSC) dysfunction is typical for different progeroid phenotypes in mice with genomic DNA repair defects. MtDNA mutagenesis in mice with defective Polg exonuclease activity also leads to progeroid symptoms, by an unknown mechanism. We found that Polg-Mutator mice had neural (NSC) and hematopoietic progenitor (HPC) dysfunction already from embryogenesis. NSC self-renewal was decreased in vitro, and quiescent NSC amounts were reduced in vivo. HPCs showed abnormal lineage differentiation leading to anemia and lymphopenia. N-acetyl-L-cysteine treatment rescued both NSC and HPC abnormalities, suggesting that subtle ROS/redox changes, induced by mtDNA mutagenesis, modulate SSC function. Our results show that mtDNA mutagenesis affected SSC function early but manifested as respiratory chain deficiency in nondividing tissues in old age. Deletor mice, having mtDNA deletions in postmitotic cells and no progeria, had normal SSCs. We propose that SSC compartment is sensitive to mtDNA mutagenesis, and that mitochondrial dysfunction in SSCs can underlie progeroid manifestations.