2. Academic Validation
  3. Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy

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

  • Nature. 2025 Nov 12. doi: 10.1038/s41586-025-09745-x.
Yifan Zhang # 1 2,  Xiao Shen # 1 2,  Yuan Shen # 1 2,  Chao Wang # 1 2,  Chengping Yu 1 2,  Jiangxue Han 1 2,  Siyi Cao 1 2,  Lin Qian 1 2,  Miaolian Ma 3,  Shijing Huang 4,  Wenyu Wen 4,  Miao Yin 1 2,  Qun-Ying Lei 5 6 7
Affiliations

Affiliations

  • 1 Fudan University Shanghai Cancer Center & School of Basic Medical Sciences & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; Shanghai Key Laboratory of Radiation Oncology; The Shanghai Key Laboratory of Medical Epigenetics; State Key Laboratory of Brain Function and Disorders, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 3 National Key Laboratory of Plant Molecular Genetics, Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai, China.
  • 4 Department of Neurosurgery, Huashan Hospital, the Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, National Center for Neurological Disorders, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 5 Fudan University Shanghai Cancer Center & School of Basic Medical Sciences & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; Shanghai Key Laboratory of Radiation Oncology; The Shanghai Key Laboratory of Medical Epigenetics; State Key Laboratory of Brain Function and Disorders, School of Basic Medical Sciences, Fudan University, Shanghai, China. [email protected].
  • 6 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. [email protected].
  • 7 New Cornerstone Science Laboratory, Frontier Innovation Center, School of Basic Medical Sciences, Fudan University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41225001 DOI: 10.1038/s41586-025-09745-x
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.

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