复旦大学雷群英小组的一项最新研究探明了胞质乙酰辅酶A是一种控制线粒体自噬的信号代谢产物。相关论文于2025年11月12日发表在《自然》杂志上。

本研究发现，通过短期禁食和抑制ATP-柠檬酸裂解酶（ACLY编码）、线粒体柠檬酸/苹果酸反转运酶（SLC25A1编码）或酰基-辅酶A合成酶短链家族成员2 （ACSS2编码），细胞内AcCoA水平降低后可触发线粒体自噬，而补充乙酸可抵消线粒体自噬。值得注意的是，NOD样受体（NLR）家族成员X1 （NLRX1）介导了这一作用。在体外和体内，破坏NLRX1可消除胞内AcCoA还原诱导的有丝分裂。从机械上讲，线粒体外膜定位的NLRX1在其富含亮氨酸重复序列（LRR）结构域的保守口袋内直接与细胞质AcCoA结合。

此外，AcCoA结合LRR结构域并增强其与核苷酸结合和寡聚化（NACHT）结构域的相互作用，有助于维持NLRX1的自抑制状态，并阻止NLRX1与轻链3 （LC3）的关联。

此外，课题组发现AcCoA–NLRX1轴是KRAS抑制剂诱导的线粒体自噬反应的基础，并促进耐药性，提供了KRAS抑制剂耐药的代谢机制。其中，胞质AcCoA是一种信号代谢物，通过其受体NLRX1将代谢与线粒体自噬联系起来。

据悉，乙酰辅酶A（acetyl - coa, AcCoA）位于营养代谢的下一个环节，穿梭于规范和非规范三羧酸循环之间，受营养状态（如禁食）的动态调节。

附：英文原文

Title: Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy

Author: Zhang, Yifan, Shen, Xiao, Shen, Yuan, Wang, Chao, Yu, Chengping, Han, Jiangxue, Cao, Siyi, Qian, Lin, Ma, Miaolian, Huang, Shijing, Wen, Wenyu, Yin, Miao, Lei, Qun-Ying

Issue&Volume: 2025-11-12

Abstract: Acetyl-coenzyme A (AcCoA) sits at the nexus of nutrient metabolism and shuttles between the canonical and non-canonical tricarboxylic acid cycle1,2, which is dynamically regulated by nutritional status, such as fasting3. Here we find that mitophagy is triggered after a reduction in cytosolic AcCoA levels through short-term fasting and through inhibition of ATP-citrate lyase (encoded by ACLY), mitochondrial citrate/malate antiporter (encoded by SLC25A1) or acyl-CoA synthetase short chain family member 2 (encoded by ACSS2), and the mitophagy can be counteracted by acetate supplementation. Notably, NOD-like receptor (NLR) family member X1 (NLRX1) mediates this effect. Disrupting NLRX1 abolishes cytosolic AcCoA reduction-induced mitophagy both in vitro and in vivo. Mechanically, the mitochondria outer-membrane-localized NLRX1 directly binds to cytosolic AcCoA within a conserved pocket on its leucine-rich repeat (LRR) domain. Moreover, AcCoA binds to the LRR domain and enhances its interaction with the nucleotide-binding and oligomerization (NACHT) domain, which helps to maintain NLRX1 in an autoinhibited state and prevents the association between NLRX1 and light chain 3 (LC3). Furthermore, we find that the AcCoA–NLRX1 axis underlies the KRAS-inhibitor-induced mitophagy response and promotes drug resistance, providing a metabolic mechanism of KRAS inhibitor resistance. Thus, cytosolic AcCoA is a signalling metabolite that connects metabolism to mitophagy through its receptor NLRX1.

DOI: 10.1038/s41586-025-09745-x

Source: https://www.nature.com/articles/s41586-025-09745-x