Mitochondrial dysfunction by TFAM depletion disrupts self-renewal and lineage differentiation of human PSCs by affecting cell proliferation and YAP response.
Mitochondrial dysfunction by TFAM depletion disrupts self-renewal and lineage differentiation of human PSCs by affecting cell proliferation and YAP response.
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TFAM 耗竭导致的线粒体功能障碍通过影响细胞增殖和 YAP 反应来破坏人类 PSC 的自我更新和谱系分化
DOI：
10.1016/j.redox.2022.102248
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发表时间：
2022-04
期刊：
影响因子：
11.4
通讯作者：
Zhang D
中科院分区：
文献类型：
--
作者：
Qi Y;Ye Y;Wang R;Yu S;Zhang Y;Lv J;Jin W;Xia S;Jiang W;Li Y;Zhang D
遗传性线粒体功能障碍常与多种胚胎发育缺陷相关。然而，线粒体如何对早期发育和细胞命运决定做出贡献的研究很少，特别是在人类中。我们利用人多能干细胞(HPSCs)，建立了Dox诱导的线粒体功能障碍的基因敲除模型，并评价了线粒体功能障碍对人类多能性维持和谱系分化的影响。核编码基因TFAM(转录因子A，线粒体)是线粒体基因转录和线粒体DNA复制所必需的，是构建线粒体功能障碍模型的靶点。TFAM缺失的hPSCs表现为线粒体DNA水平和氧化呼吸效率降低，表现为典型的线粒体功能障碍表型。线粒体功能障碍导致hPSCs的自我更新功能受损，原因是增殖受阻。虽然线粒体功能障碍并不影响多能基因的表达，但它会导致谱系分化的严重缺陷。对中胚层分化的进一步研究表明，线粒体功能障碍导致增殖障碍和YAP核转位，从而共同阻止中胚层谱系分化。这些发现为理解线粒体在人类多能性维持和中胚层分化中的功能提供了新的见解。
Genetic mitochondrial dysfunction is frequently associated with various embryonic developmental defects. However, how mitochondria contribute to early development and cell fate determination is poorly studied, especially in humans. Using human pluripotent stem cells (hPSCs), we established a Dox-induced knockout model with mitochondrial dysfunction and evaluated the effect of mitochondrial dysfunction on human pluripotency maintenance and lineage differentiation. The nucleus-encoded gene TFAM (transcription factor A, mitochondrial), essential for mitochondrial gene transcription and mitochondrial DNA replication, is targeted to construct the mitochondrial dysfunction model. The hPSCs with TFAM depletion exhibit the decrease of mtDNA level and oxidative respiration efficiency, representing a typical mitochondrial dysfunction phenotype. Mitochondrial dysfunction leads to impaired self-renewal in hPSCs due to proliferation arrest. Although the mitochondrial dysfunction does not affect pluripotent gene expression, it results in a severe defect in lineage differentiation. Further study in mesoderm differentiation reveals that mitochondrial dysfunction causes proliferation disability and YAP nuclear translocalization and thus together blocks mesoderm lineage differentiation. These findings provide new insights into understanding the mitochondrial function in human pluripotency maintenance and mesoderm differentiation.
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影响因子：
4.6
作者：
Tani H;Ohnishi S;Shitara H;Mito T;Yamaguchi M;Yonekawa H;Hashizume O;Ishikawa K;Nakada K;Hayashi JI
通讯作者：
Hayashi JI
影响因子：
4.6
作者：
Lees, Jarmon G.;Gardner, David K.;Harvey, Alexandra J.
通讯作者：
Harvey, Alexandra J.
影响因子：
7.1
作者：
Fernandez-Marcos, Pablo J.;Auwerx, Johan
通讯作者：
Auwerx, Johan
影响因子：
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作者：
Guo J;Zheng L;Liu W;Wang X;Wang Z;Wang Z;French AJ;Kang D;Chen L;Thibodeau SN;Liu W
通讯作者：
Liu W
DOI：
10.1080/21691401.2018.1431654
发表时间：
2018-01-01
影响因子：
5.8
作者：
Chen, Xiangrong;Li, Shun;Guo, Xieli
通讯作者：
Guo, Xieli