News Release

Researchers reveal role of protein oxidative folding in stem cell aging

Peer-Reviewed Publication

Chinese Academy of Sciences Headquarters

It has been widely acknowledged for a long time that mitochondria are the main source of reactive oxygen species (ROS). However, the role of endoplasmic reticulum (ER)-generated ROS has not been extensively studied even though oxidative protein folding in the ER has been estimated to contribute approximately 25% of cellular ROS during protein synthesis. 

Now a major study by Prof. WANG Lei and WANG Chih-chen’s group at the Institute of Biophysics (IBP) of the Chinese Academy of Sciences (CAS) and Prof. LIU Guanghui’s group at the Institute of Zoology (IOZ) of CAS has shed light on the role of ER-generated ROS in cell senescence. 

Their research article, “Reducing oxidative protein folding alleviates senescence by minimizing ER-to-nucleus H2O2 release,” was published in EMBO Reports.  

The study establishes the relationship between oxidative protein folding and stem cell aging for the first time. It observed that the hydrogen peroxide (H2O2), which is generated by oxidative protein folding in the ER, can be released to the nucleus, thereby inducing the expression of SERPINE1, a key factor promoting cell senescence. 

The researchers found that protein disulfide isomerase (PDI), a key oxidoreductase that catalyzes oxidative protein folding, accumulates in aged human cells and the livers of mice. They also observed that depletion of PDI alleviated cell senescence. By using an ultra-sensitive, genetically encoded fluorescence probe, the researchers further showed that PDI deficiency slowed the rate of oxidative protein folding and reduced the level of its byproduct H2O2 both in the ER and the nucleus. Through omics analysis, the researchers found that PDI deficiency causes the downregulation of SERPINE1, an aging-related molecule regulated by H2O2, thereby alleviating the senescence of stem cells. 

The researchers also showed that knockdown of PDI in various human cell models can delay senescence, indicating that PDI may be a potential molecular target for alleviating aging. 

Previous studies have revealed that reducing gene transcription and protein synthesis alleviate senescence. This study provides new ideas and molecular targets for understanding aging from the perspective of protein folding, suggesting that in order to achieve the sustainable development of individuals (i.e., keeping them younger), cells should improve energy efficiency and emission reduction (i.e., reducing oxidative protein folding). 

Dr. CHENG Fang from IBP and Dr. JI Qianzhao from IOZ are the co-first authors of the paper. Profs. WANG Lei and LIU Guanghui are the co-corresponding authors. The study is supported by the National Key R&D Program of China, the National Natural Science Foundation of China, the Strategic Priority Research Program of CAS and the Youth Innovation Promotion Association of CAS. 

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