PGRMC2 is an intracellular haem chaperone critical for adipocyte function

Area of Science:

• Cellular Biology
• Metabolic Health
• Biochemistry

Background:

• Haem is vital for protein function and cellular signaling.
• Intracellular transport pathways for haem are not fully understood.
• Mitochondria synthesize haem, but its delivery to cellular targets is poorly defined.

Purpose of the Study:

• To investigate the role of progesterone receptor membrane component 2 (PGRMC2) in intracellular haem transport.
• To elucidate the function of PGRMC2 in adipose tissue and its impact on metabolic processes.

Main Methods:

• Investigated PGRMC2 function in brown adipose tissue using knockout mice.
• Assessed nuclear labile haem levels, stability of haem-responsive transcriptional repressors (Rev-Erbα and BACH1), and gene expression.
• Utilized a small-molecule PGRMC2 activator in obese-diabetic mice.

Main Results:

• PGRMC2 deletion in brown fat reduced nuclear labile haem and increased Rev-Erbα and BACH1 stability.
• PGRMC2 deficiency led to mitochondrial defects, impaired adaptive thermogenesis, and exacerbated metabolic deterioration on a high-fat diet.
• PGRMC2 activator treatment improved diabetic features in obese mice.

Conclusions:

• PGRMC2 is essential for intracellular haem transport, particularly to the nucleus.
• Adipose tissue haem dynamics, mediated by PGRMC2, significantly influence systemic physiology.
• PGRMC2 modulation presents a potential therapeutic strategy for obesity-linked metabolic disorders.