HMGB1 Modulates Decidualization Through PPARGC1A and Mitochondrial Bioenergetics

Area of Science:

• Reproductive biology
• Cellular and molecular medicine
• Mitochondrial biology

Background:

• Endometrial decidualization is vital for embryo implantation and pregnancy.
• Recurrent spontaneous abortion (RSA) involves decidual dysfunction.
• The role of High Mobility Group Box 1 (HMGB1) in decidualization is not fully understood.

Purpose of the Study:

• To investigate the role of HMGB1 in human endometrial stromal cells (hESCs) during decidualization.
• To explore the HMGB1-mediated mechanisms regulating mitochondrial function and metabolism in decidualization.
• To assess the association of HMGB1 with recurrent spontaneous abortion (RSA).

Main Methods:

• In vitro decidualization of hESCs with HMGB1 manipulation (knockdown).
• Analysis of gene and protein expression (PRL, IGFBP1, PPARGC1A).
• Assessment of mitochondrial function (oxidative phosphorylation, ATP production, morphology, membrane potential).
• In vivo studies in early pregnant mice.

Main Results:

• HMGB1 expression is upregulated during in vitro and in vivo decidualization but reduced in RSA decidua.
• HMGB1 knockdown impairs hESC differentiation, reduces PRL and IGFBP1, and promotes proliferation.
• HMGB1 deficiency leads to mitochondrial dysfunction and impaired ATP production.
• HMGB1 regulates PPARGC1A expression, linking it to mitochondrial biogenesis and metabolism.
• Reduced PPARGC1A expression is observed in RSA decidua.

Conclusions:

• HMGB1 is a key regulator of endometrial decidualization, essential for mitochondrial function and cellular energy metabolism.
• The HMGB1-PPARGC1A axis plays a critical role in metabolic regulation during decidualization.
• Dysregulation of the HMGB1-PPARGC1A pathway may contribute to decidual dysfunction and pregnancy complications like RSA.