Schmitz Daniel A, Oura Seiya, Li Leijie, Ding Yi, Dahiya Rashmi, Ballard Emily, Pinzon-Arteaga Carlos, Sakurai Masahiro, Okamura Daiji, Yu Leqian, Ly Peter, Wu Jun
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Cell. 2025 Jun 5. doi: 10.1016/j.cell.2025.05.020.
Mitochondrial abundance and genome are crucial for cellular function, with disruptions often associated with disease. However, methods to modulate these parameters for direct functional dissection remain limited. Here, we eliminate mitochondria from pluripotent stem cells (PSCs) by enforced mitophagy and show that PSCs survived for several days in culture without mitochondria. We then leverage enforced mitophagy to generate interspecies PSC fusions that harbor either human or non-human hominid (NHH) mitochondrial DNA (mtDNA). Comparative analyses indicate that human and NHH mtDNA are largely interchangeable in supporting pluripotency in these PSC fusions. However, species divergence between nuclear and mtDNA leads to subtle species-specific transcriptional and metabolic variations. By developing a transgenic enforced mitophagy approach, we further show that reducing mitochondrial abundance leads to delayed development in pre-implantation mouse embryos. Our study opens avenues for investigating the roles of mitochondria in development, disease, and interspecies biology.
线粒体丰度和基因组对细胞功能至关重要，其破坏往往与疾病相关。然而，用于直接功能剖析以调节这些参数的方法仍然有限。在这里，我们通过强制线粒体自噬从多能干细胞（PSC）中消除线粒体，并表明PSC在没有线粒体的情况下在培养中存活了几天。然后，我们利用强制线粒体自噬产生携带人类或非人类原始人类（NHH）线粒体DNA（mtDNA）的种间PSC融合体。比较分析表明，人类和NHH mtDNA在支持这些PSC融合体的多能性方面在很大程度上是可互换的。然而，核DNA和mtDNA之间的物种差异导致了微妙的物种特异性转录和代谢变化。通过开发一种转基因强制线粒体自噬方法，我们进一步表明，降低线粒体丰度会导致植入前小鼠胚胎发育延迟。我们的研究为研究线粒体在发育、疾病和种间生物学中的作用开辟了途径。
