Mineralocorticoid receptor phase separation modulates cardiac preservation

Area of Science:

• Transplantation Biology
• Molecular Mechanisms of Organ Preservation
• Biochemistry

Background:

• Heart transplantation is a critical treatment for end-stage heart failure.
• Donor organ shortage is a major limitation, exacerbated by short cold ischemic times.
• Understanding cellular mechanisms during cold storage is vital for improving organ viability.

Purpose of the Study:

• To investigate the role of mineralocorticoid receptor (MR) phase separation in donor heart injury during cold storage.
• To explore pharmacological modulation of MR phase separation for enhanced organ preservation.
• To determine if macromolecular phase separation is a broader phenomenon in other solid organs during preservation.

Main Methods:

• Investigated MR expression and phase separation in murine and human donor hearts subjected to cold storage.
• Utilized pharmacological inhibition to assess the impact on heart preservation quality.
• Examined phase separation of transcriptional regulators (MR, HDAC1, BRD4) in cold-preserved lung, liver, and kidney tissues.

Main Results:

• Identified mineralocorticoid receptor (MR) phase separation in donor cardiomyocytes during cold storage, contributing to injury.
• Demonstrated that pharmacological inhibition of MR can improve donor heart preservation.
• Observed similar phase separation phenomena involving other transcriptional regulators in cold-preserved lung, liver, and kidney.

Conclusions:

• Mineralocorticoid receptor (MR) phase separation is a key factor in donor organ injury during cold preservation.
• Targeting MR phase separation presents a novel therapeutic strategy to improve solid organ preservation.
• Macromolecular phase separation is a conserved biological process during cold storage across multiple organs.