Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru 560064, India.
Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru 560064, India; Institute for Stem Cell Biology and Regenerative Medicine, Bengaluru 560065, India.
Stem Cell Reports. 2018 Jul 10;11(1):128-141. doi: 10.1016/j.stemcr.2018.05.015. Epub 2018 Jun 21.
Pluripotent stem cells (PSCs) derive energy predominantly from glycolysis and not the energy-efficient oxidative phosphorylation (OXPHOS). Differentiation is initiated with energy metabolic shift from glycolysis to OXPHOS. We investigated the role of mitochondrial energy metabolism in human PSCs using molecular, biochemical, genetic, and pharmacological approaches. We show that the carcinoma protein OCIAD1 interacts with and regulates mitochondrial complex I activity. Energy metabolic assays on live pluripotent cells showed that OCIAD1-depleted cells have increased OXPHOS and may be poised for differentiation. OCIAD1 maintains human embryonic stem cells, and its depletion by CRISPR/Cas9-mediated knockout leads to rapid and increased differentiation upon induction, whereas OCIAD1 overexpression has the opposite effect. Pharmacological alteration of complex I activity was able to rescue the defects of OCIAD1 modulation. Thus, hPSCs can exist in energy metabolic substates. OCIAD1 provides a target to screen for additional modulators of mitochondrial activity to promote transient multipotent precursor expansion or enhance differentiation.
多能干细胞（PSCs）主要通过糖酵解获取能量，而不是通过高效的氧化磷酸化（OXPHOS）。分化是从糖酵解到 OXPHOS 的能量代谢转变开始的。我们使用分子、生化、遗传和药理学方法研究了线粒体能量代谢在人 PSCs 中的作用。我们表明，癌蛋白 OCIAD1 与线粒体复合物 I 活性相互作用并调节其活性。对活多能细胞进行的能量代谢分析表明，OCIAD1 耗尽的细胞具有更高的 OXPHOS，并且可能处于分化状态。OCIAD1 维持人类胚胎干细胞，其通过 CRISPR/Cas9 介导的敲除而耗尽会导致在诱导时快速且增加的分化，而 OCIAD1 的过表达则产生相反的效果。复合物 I 活性的药理学改变能够挽救 OCIAD1 调节的缺陷。因此，hPSCs 可以存在于能量代谢亚状态中。OCIAD1 提供了一个靶标，可用于筛选其他线粒体活性调节剂，以促进短暂的多能前体扩增或增强分化。
