Mitochondria are not only known as the "energy factories" of cells but also serve as critical "signal hubs" regulating vital processes such as aging, immunity, cell proliferation, and apoptosis. Intriguingly, studies in model organisms including nematodes, fruit flies, and mice have demonstrated that mild and persistent mitochondrial stress can actually promote longevity. In nematodes, mitochondrial stress enhances the organism’s ability to resist environmental stress by regulating nuclear gene expression, thereby facilitating mitochondrial damage repair and metabolic reprogramming. Previously, the research group led by Ye Tian from the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, discovered that mitochondrial stress can regulate chromatin states through the epigenetic factor NuRD (Nucleosome Remodeling and Deacetylase) complex, thereby conferring a longevity phenotype. However, the mechanism by which the NuRD complex senses and responds to mitochondrial signals remained elusive.
On August 13, 2025, Ye Tian's research group published a study in SCIENCE CHINA Life Sciences titled "Mitochondrial Stress Orchestrates Chromatin Remodeling and Longevity via Phosphoregulation of the NuRD Component LIN-40". Using the model organism Caenorhabditis elegans, the study revealed a new mechanism of mitochondrial-nuclear signal communication: under mitochondrial stress, the core component of the NuRD complex, LIN-40/MTA, undergoes dephosphorylation at a specific site (T654). This modification is indispensable for chromatin condensation and lifespan extension under mitochondrial stress conditions.
Key highlights of the research include the following: first, the team isolated the NuRD complex under mitochondrial stress using protein purification techniques. Through proteomic analysis, they found that LIN-40 (a homolog of MTA), a core component of the NuRD complex, undergoes dephosphorylation at the specific phosphorylation site (T654) under stress. Subsequently, using genetic and biochemical experimental methods, they identified the kinase PMK-3 and phosphatase GSP-2 that regulate the dephosphorylation of LIN-40/MTA. Finally, they proposed that dephosphorylation at this site enhances the interaction between LIN-40/MTA and DVE-1, a key transcription factor regulating mitochondrial stress, thereby precisely modulating mitochondrial stress-related genes. This study not only reveals an important link between mitochondrial signals and epigenetic regulation but also provides new insights into the molecular mechanisms underlying stress adaptation and lifespan extension.
The study was co-first-authored by Jun Zhou and Di Zhu, graduated PhD students from Ye Tian's group. Yibing Wang (a current PhD student), Zilun Wang (a visiting student), Ning Zhang (a graduated PhD student), Yiqian Zhang (a visiting student), and Xiahe Huang (a senior engineer from Yingchun Wang's group) made important contributions to the experimental implementation and data analysis. Ye Tian (researcher) and Xueying Wu (associate researcher) served as co-corresponding authors, responsible for project design, research guidance, and manuscript writing. This work was supported by the National Key R&D Program, the Strategic Priority Research Program (Category B) of the Chinese Academy of Sciences, projects from the National Natural Science Foundation of China, the Stable Support for Basic Research Youth Team Program of the Chinese Academy of Sciences, the Youth Innovation Promotion Association of the Chinese Academy of Sciences, and the New Cornerstone Science Foundation.