St John Justin C, Ramalho-Santos João, Gray Heather L, Petrosko Patti, Rawe Vanesa Y, Navara Christopher S, Simerly Calvin R, Schatten Gerald P
The Mitochondrial and Reproductive Genetics Group, Division of Medical Sciences, University of Birmingham, Birmingham, United Kingdom.
Cloning Stem Cells. 2005;7(3):141-53. doi: 10.1089/clo.2005.7.141.
Mitochondrial biogenesis and activation of both oxidative phosphorylation, as well as transcription and replication of the mitochondrial genome, are key regulatory events in cell differentiation. Mitochondrial DNA transcription and replication are highly dependent on the interaction with nuclear-encoded transcription factors translocated from the nucleus. Using a human embryonic stem cell line, HSF 6, we analyzed the proliferation of mitochondria and the expression of mtDNA-specific transcription factors in undifferentiated, migratory embryonic stem cells and spontaneously derived cardiomyocytes. Mitochondrial proliferation and mtDNA transcription are initiated in human embryonic stem cells as they undergo spontaneous differentiation in culture into beating cardiomyocytes. Undifferentiated, pluripotent human embryonic stem cells have few mitochondria, and, as they differentiate, they polarize to one extremity of the cell and then bipolarize the differentiating cell. The differentiated cell then adopts the cytoplasmic configuration of a somatic cell as evidenced in differentiating cardiomyocytes. Transcription and replication of the extranuclear mitochondrial genome is dependent on nuclear encoded factors exported to the mitochondrion. However, the differentiating cardiomyocytes have reduced or absent levels of these transcription and replication factors, namely mitochondrial transcription factors A, B1, B2, and nuclear respiratory factor 1 and polymerase gamma. Therefore, final embryonic stem cell commitment may be influenced by mitochondrial proliferation and mtDNA transcription. However, it is likely that differentiating cardiomyocytes are in mitochondrial arrest, awaiting commitment to a final cell fate.
线粒体生物合成以及氧化磷酸化的激活，还有线粒体基因组的转录和复制，都是细胞分化过程中的关键调控事件。线粒体DNA的转录和复制高度依赖于与从细胞核转运而来的核编码转录因子的相互作用。我们使用人胚胎干细胞系HSF 6，分析了未分化的、迁移性胚胎干细胞以及自发分化而来的心肌细胞中线粒体的增殖情况以及线粒体DNA特异性转录因子的表达。当人胚胎干细胞在培养过程中自发分化为跳动的心肌细胞时，线粒体增殖和线粒体DNA转录开始启动。未分化的、多能的人胚胎干细胞线粒体数量很少，在分化过程中，它们会极化到细胞的一端，然后使分化中的细胞两极化。随后，分化后的细胞呈现出体细胞的细胞质结构，这在分化中的心肌细胞中得到了证实。核外线粒体基因组的转录和复制依赖于输出到线粒体的核编码因子。然而，分化中的心肌细胞中这些转录和复制因子，即线粒体转录因子A、B1、B2，以及核呼吸因子1和聚合酶γ的水平降低或缺失。因此，胚胎干细胞的最终分化可能受线粒体增殖和线粒体DNA转录的影响。然而，分化中的心肌细胞可能处于线粒体停滞状态，等待确定最终的细胞命运。
