The Acetyl‐CoA‐NLRX1 Axis Acts as a Key Player in Mitophagy and Drug Resistance

Zhang et al. reported in Nature that cytosolic Acetyl-Coenzyme A (AcCoA) directly bound the NOD-like receptor (NLR) family member X1 (NLRX1) to gate mitophagy at the outer mitochondrial membrane [1]. The authors showed this metabolite-sensing switch shaped Kirsten rat sarcoma viral oncogene homolog (KRAS)-inhibitor responses and contributes to drug resistance. Mitophagy is a selective form of autophagy that removes damaged or superfluous mitochondria, limiting reactive oxygen species accumulation and preserving bioenergetic fitness. It can be initiated through ubiquitin-dependent routes (classically involving PINK1/Parkin) or receptor-mediated pathways in which OMM proteins recruit autophagy machinery, most notably light chain 3 (LC3)-family proteins, to engulf mitochondria within autophagosomes. The authors expanded this framework by positioning NLRX1 as a metabolite-gated mitophagy receptor, and by identifying cytosolic AcCoA as a dynamic signal that controls whether NLRX1 is “available” to engage the autophagy apparatus [1]. Mechanistically, cytosolic AcCoA maintained nucleotide-binding and oligomerization (NLRX1) in an autoinhibited state by occupying a conserved pocket within its leucine-rich repeat (LRR) domain. The authors showed that AcCoA binding strengthens intramolecular contacts between the LRR and NACHT domains, effectively “locking” NLRX1 and preventing its association with LC3 (Figure 1). Under conditions in which cytosolic AcCoA declines, this ligand-dependent clamp was released, allowing conformational changes and oligomerization that enable NLRX1 to recruit LC3 and initiate mitophagy. Furthermore, the authors demonstrated that the AcCoA-NLRX1 axis was essential for the KRAS inhibitor-induced mitophagy and promoted adaptive drug resistance. Importantly, NLRX1 sensed dynamic fluctuations in cytosolic AcCoA under metabolic stress (e.g., nutrient deprivation or drug exposure), revealing a signaling function of AcCoA that was independent of acetylation modifications or AMP-activated protein kinase/mammalian target of rapamycin AMPK/mTOR pathways. Collectively, these findings nominated the AcCoA-NLRX1-mitophagy axis as a potential therapeutic vulnerability and suggested a combinatorial strategy to enhance the efficacy of KRAS inhibitors in the context of cancer metabolic rewiring. AcCoA was a central metabolite involved in energy production, biosynthesis, and key metabolic pathways like the tricarboxylic acid cycle, fatty acid synthesis, and protein acetylation [2]. In this study, the authors identified cytosolic AcCoA as a key signaling metabolite regulating mitophagy [1]. In many cells, cytosolic AcCoA is generated largely from citrate exported out of mitochondria and cleaved by ATP citrate lyase (ACLY), while mitochondrial citrate handling is influenced by transporters such as solute carrier family 25 member 1 (SLC25A1), often referred to as the mitochondrial citrate carrier. The authors showed that a reduction in cytosolic AcCoA levels, triggered by fasting or by inhibition of enzymes such as ACLY and SLC25A1, induced mitophagy in multiple cell types. Moreover, this effect was reversible by acetate supplementation, suggesting that cytosolic AcCoA levels were critical for the activation of mitophagic processes. In vivo experiments in mice further supported these observations, showing fasting-induced mitophagy in tissues such as the brain and gastrocnemius, but not the liver. Taken together, cytosolic AcCoA levels regulated mitophagy both in vitro and in vivo. NLRX1 is the only known NLR localized to the mitochondria, and previous work showed that it mediated mitophagy under conditions such as bacterial infection [3]. Using a whole-genome CRISPR/Cas9 screen, the researchers identified NLRX1 as the key mediator in a mitophagy model induced by reduced cytosolic AcCoA levels. When nutrients were abundant, high concentrations of cytosolic AcCoA acted like a “brake” by binding NLRX1 and locking it in an autoinhibited state, thereby preventing interaction with the autophagy protein LC3. When nutrients were scarce, cytosolic AcCoA levels decreased, releasing this “brake” and promoting NLRX1 conformational changes and oligomerization; NLRX1 then recruited and bound LC3, initiating mitophagy. This discovery positioned NLRX1 as a crucial mitophagy receptor and expanded our understanding of how cellular metabolic state influences mitochondrial quality control. The authors validated these observations in vivo. In mice, fasting reduced cytosolic AcCoA and induced mitophagy in specific tissues, including the gastrocnemius muscle and brain [1]. Interestingly, fasting did not elicit a comparable mitophagy response in liver tissue, suggesting tissue-specific regulation of mitophagy via AcCoA. These differential tissue responses may have reflected variations in AcCoA metabolism and availability. For example, the liver's strong capacity for acetate utilization, ketogenesis, and rapid metabolic adaptation might buffer cytosolic AcCoA fluctuations relative to muscle or brain, thereby reducing the trigger for NLRX1-dependent mitophagy. Data from NLRX1 knockout mice further confirmed that NLRX1 was essential for fasting-induced mitophagy. Together, the results provided direct evidence that cytosolic AcCoA reduction, acting through its receptor NLRX1, served as a critical metabolic signal for mitophagy in vivo. This study also linked metabolic reprogramming, a hallmark of cancer, to mitophagy and drug resistance. KRAS mutations were prevalent in cancers such as pancreatic ductal adenocarcinoma [4, 5]. In the context of KRAS inhibitor (KRASi)-induced resistance, the authors showed that AcCoA reduction and subsequent NLRX1-mediated mitophagy contributed to drug resistance in KRAS-mutant tumors [1]. KRASi-induced decreases in AcCoA triggered mitophagy via NLRX1, facilitating the cancer cells' survival under therapeutic stress. Disrupting this pathway, either by targeting AcCoA metabolism or NLRX1 itself, potentiated the anti-cancer effects of KRASi. These findings suggested a potential avenue to overcome KRASi resistance by targeting the AcCoA-NLRX1-mitophagy axis. In summary, Zhang et al. presented a novel perspective on cytosolic AcCoA as a metabolite signal that regulates mitophagy through the NLRX1 receptor [1]. This discovery expanded the conceptual repertoire of metabolite signaling, established a nutrient-responsive checkpoint for receptor-mediated mitophagy, and offers a mechanistic explanation for how metabolic perturbations – whether physiological (fasting) or pharmacological (KRAS inhibition) – can reshape mitochondrial homeostasis. Looking forward, several avenues merit further investigation. First, metabolic modulators that influence AcCoA levels could have served as adjuncts to cancer therapies, particularly those targeting KRAS-driven malignancies. Second, small molecules that enhanced the interaction between NLRX1 and AcCoA or disrupted NLRX1 binding to LC3 could have inhibited mitophagy and sensitized cancer cells to chemotherapy or targeted therapies. Finally, using NLRX1 as a biomarker of mitophagic activity in response to metabolic stress could have offered new diagnostic opportunities in cancer and metabolic diseases. Ping Jin: writing – original draft, funding acquisition. Biao Hu: visualization. Jingwen Jiang: writing – review and editing, funding acquisition. Li Xu: conceptualization, supervision, funding acquisition. All authors have read and approved the final manuscript. Figures are created using BioRender.com. This work was supported by the Basic Research Program from Yunnan Science and Technology Department (202401CF070184); Sichuan Science and Technology Department (2025NSFJQ0035); and Yunnan Province Xingdian Talent Support Program (C619300A171). The authors have nothing to report. The authors declare no conflicts of interest. The authors have nothing to report.