The dual role of PGAM5 in inflammation

Abstract

In recent years, the focus on human inflammation in research has increased, with aging-related inflammation widely recognized as a defining characteristic of aging. Inflammation is strongly correlated with mitochondrial dysfunction. Phosphoglycerate mutase family member 5 (PGAM5) is a novel modulator of mitochondrial homeostasis in response to mechanical stimulation. Here we review the structure and sublocalization of PGAM5, introduce its importance in programmed cell death and summarize its crucial roles in the development and progression of inflammatory diseases such as pneumonia, hepatitis, neuroinflammation and aging. Notably, PGAM5 has dual effects on controlling inflammation: distinct PGAM5-mediated mitochondrial functions exhibit cellular heterogeneity, leading to its dual functions in inflammation control. We therefore highlight the double-edged sword nature of PGAM5 as a potential critical regulator and innovative therapeutic target in inflammation. Finally, the challenges and future directions of the use of PGAM5, which has dual properties, as a target molecule in the clinic are discussed. This review provides crucial insights to guide the development of intelligent therapeutic strategies targeting PGAM5-specific regulation to treat intractable inflammatory conditions, as well as the potential extension of its broader application to other diseases to achieve more precise and effective treatment outcomes. This Review explores the role of the PGAM5 protein in inflammation and aging and investigates how PGAM5 affects mitochondrial function and inflammation. The authors review various experiments showing that PGAM5 can both promote and reduce inflammation by influencing processes such as mitochondrial fission and mitophagy, which are crucial for maintaining cell health. This research highlights that PGAM5 interacts with other proteins to regulate cell death and inflammation. The findings suggest that PGAM5 has a dual role: it can either worsen or alleviate inflammation depending on the context. This dual nature makes it a potential target for treating inflammatory diseases. Future research could focus on developing therapies that modulate PGAM5 activity to treat conditions such as arthritis or neurodegenerative diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.