霍华德休斯医学院Shingo Kajimura小组的最新研究提出了线粒体通过PEP梭体控制甘油脂合成。这一研究成果发表在2026年3月17日出版的国际学术期刊《细胞》上。
课题组研究人员发现SLC25A35在利用丙酮酸-PEP旁路的脂肪生成细胞中调节线粒体PEP外排和甘油生成。重构和结构研究表明，PEP通过SLC25A35以pH梯度依赖的方式运输。脂肪细胞中SLC25A35的缺失损害了线粒体PEP向甘油-3-磷酸的转化，从而减少了甘油脂的合成。在肥胖小鼠中，肝脏抑制SLC25A35可减轻脂肪变性，改善全身葡萄糖稳态。总之，这些结果表明，线粒体通过SLC25A35提供PEP促进甘油脂合成，提供了脂肪生成线粒体作为限制甘油脂合成的靶点，这是肝脂肪变性和2型糖尿病发病机制的关键步骤。
据悉，线粒体除了提供ATP外，还提供多种代谢物，以满足细胞的特定需要。其中一种代谢物是磷酸烯醇丙酮酸（PEP），它含有比ATP更高能量的磷酸键，具有多种生物功能。然而，线粒体产生的PEP如何传递到细胞质并满足细胞特异性需求仍然是未知的。
附：英文原文
Title: Mitochondrial control of glycerolipid synthesis by a PEP shuttle
Author: Tadashi Yamamuro, Daisuke Katoh, Guilherme Martins Silva, Hiroshi Nishida, Satoshi Oikawa, Yusuke Higuchi, Dandan Wang, Masanori Fujimoto, Naofumi Yoshida, Mark Li, Jihoon Shin, Zezhou Zhao, Jin-Seon Yook, Lijun Sun, Shingo Kajimura
Issue&Volume: 2026-03-17
Abstract: Mitochondria provide a variety of metabolites, in addition to ATP, to meet cell-specific needs. One such metabolite is phosphoenolpyruvate (PEP), which contains a higher-energy phosphate bond than ATP and has diverse biological functions. However, how mitochondria-generated PEP is delivered to the cytosol and fulfills cell-specific requirements remains elusive. Here, we show that SLC25A35 regulates mitochondrial PEP efflux and glyceroneogenesis in lipogenic cells that utilize the pyruvate-to-PEP bypass. Reconstitution and structural studies demonstrated PEP transport by SLC25A35 in a pH gradient-dependent manner. Loss of SLC25A35 in adipocytes impaired the conversion of mitochondrial PEP into glycerol-3-phosphate, thereby reducing glycerolipid synthesis. Significantly, hepatic inhibition of SLC25A35 in obese mice alleviated steatosis and improved systemic glucose homeostasis. Together, these results suggest that mitochondria facilitate glycerolipid synthesis by providing PEP via SLC25A35, offering lipogenic mitochondria as a target to limit glycerolipid synthesis, a pivotal step in the pathogenesis of hepatic steatosis and type 2 diabetes.
DOI: 10.1016/j.cell.2026.02.017
Source: https://www.cell.com/cell/abstract/S0092-8674(26)00224-2