In recent years, intermittent fasting has already gone mainstream. Simply controlling eating times to maintain moderate hunger not only stabilizes blood sugar but also clears the body of aged metabolic waste.
The team led by Professor Qun-Ying Lei from School of Basic Medical Sciences, Fudan University reported on Thursday in Nature how moderate hunger triggers positive responses in the body, which, more importantly, opens up a new and imaginative frontier for future research in combating metabolic diseases, cancer, and even delaying aging. Peer reviewers highlighted the findings “opens up new insights into how metabolic status and single metabolites could directly control mitochondrial turnover”, and “are of great interest to cancer biology and immuno-oncology research community”.
If we imagine a cell as a city, mitochondria are the power plants within it. Many aging power plants (dysfunctional mitochondria) continue to operate inefficiently, emitting black smoke (producing free radicals) and polluting the urban environment (causing stress to the body).
Moderate hunger acts like an urban renewal project which initiates mitophagy— the targeted demolition of those inefficient old power plants. Acetyl-coenzyme A (AcCoA) is the “core raw material” in this city. In previous scientific understanding, although AcCoA was skilled in energy production and resource allocation, all its actions were commanded by AMPK and mTOR. However, Lei’s team discovered that AcCoA itself can initiate mitophagy without relying on instructions from AMPK and mTOR. “We want to think outside the traditional framework, and make innovations independent of classic metabolic sensing pathways,” said Lei, who has been developing this kind of conceptual innovation since 2016.
The team utilized mild starvation conditions that could mimic serum nutrient levels after fasting overnight, and was surprised to find that mitophagy was significantly activated without responses from AMPK or mTOR but dependent on cytosolic AcCoA levels. The team employed genome-wide CRISPR screening of over 20,000 genes, which ultimately pointed to a key protein—NLRX1, that was required for this response.
In both cell and mouse models, once NLRX1 was knocked out, the mitophagy triggered by decreased AcCoA completely stopped, while general autophagy remained unaffected. This proves that NLRX1 plays an irreplaceable sentinel role. To address how AcCoA transmits signals to NLRX1, Lei’s team boldly hypothesized that AcCoA and NLRX1 are directly associated.
By conducting “pull-down” experiments in complex cellular environments and more precise radioligand binding assays, they confirmed their hypothesis. When nutrients are abundant, high concentrations of AcCoA act like a “molecular brake”, precisely fitting into the LRR domain of NLRX1 and locking it in a “dormant” state, preventing the initiation of mitophagy. When nutrients are scarce or under drug-induced stress, AcCoA levels drop, releasing the brake, and the liberated NLRX1 actively recruits the autophagy protein LC3 to initiate the selective clearance of mitochondria.
“Only through interdisciplinary collaboration can we reach the true frontiers of science,” said Lei. Her team also turned their attention to KRAS—one of the most commonly mutated oncogenes in tumors, whose inhibition has faced the major clinical challenge of drug resistance. The team found that drug-induced decreases in AcCoA levels activate the mitophagy pathway centered on NLRX1, enabling tumor cells to escape drug-induced death.
Experiments confirmed that knocking out NLRX1 or using the mitophagy inhibitor Mdivi-1 significantly enhanced the anti-tumor effects of KRAS inhibitors. This suggests that combination therapy strategies targeting the AcCoA-NLRX1 axis could become a new approach to overcome drug resistance in KRAS-mutant tumors, offering new hope for cancer patients.
In the future, her team, as well as all members of the School of Basic Medical Sciences, Fudan University, will continue to make contributions to unraveling more mysteries of life and conquering major health challenges.
Co-first authors are Yifan Zhang, assistant researcher at the Fudan University Cancer Institute; Xiao Shen and Chao Wang, both doctoral candidates; and Yuan Shen, a post-doctoral fellow. Corresponding author is Qun-Ying Lei, professor at the School of Basic Medical Sciences/Fudan University Cancer Institute.
Link to the article “Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy”：https://www.nature.com/articles/s41586-025-09745-x
Presented by Fudan University Media Center
Writer: ZHOUYiting
Editor: WANG Mengqi, LI Yijie
