通过强迫线粒体自噬揭示线粒体对哺乳动物多能性的影响，这一成果由美国德克萨斯大学吴军研究团队经过不懈努力而取得。2025年出版的《细胞》杂志发表了这一最新研究成果。

研究小组通过强迫线粒体自噬消除多能干细胞（PSCs）中的线粒体，并表明PSCs在没有线粒体的培养中存活数天。然后，小组利用强制线粒体自噬来产生含有人类或非人原人（NHH）线粒体DNA （mtDNA）的种间PSC细胞。比较分析表明，人类和NHH的mtDNA在支持这些PSC细胞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，研究人员进一步表明，减少线粒体丰度导致着床前无母胚胎的发育延迟。他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道路。

研究人员表示，线粒体丰度和基因组对细胞功能至关重要，破坏通常与疾病有关。然而，调节这些参数用于直接功能解剖的方法仍然有限。

附：英文原文

Title: Unraveling mitochondrial influence on mammalian pluripotency via enforced mitophagy

Author: Daniel A. Schmitz, Seiya Oura, Leijie Li, Yi Ding, Rashmi Dahiya, Emily Ballard, Carlos Pinzon-Arteaga, Masahiro Sakurai, Daiji Okamura, Leqian Yu, Peter Ly, Jun Wu

Issue&Volume: 2025-06-010

Abstract: 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.

DOI: 10.1016/j.cell.2025.05.020

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00570-7