Mineralocorticoid receptor phase separation modulates cardiac preservation

Abstract

Heart transplantation is the gold standard treatment for patients with end-stage heart failure. However, there is a shortage of donor hearts available. The short tolerable cold ischemic time for delivering donor hearts to matching recipients is closely responsible for this shortage. Here we uncover the phenomenon of mineralocorticoid receptor (MR) phase separation, which exacerbates injury to the murine and human donor heart during cold storage and can be modulated with pharmacological inhibition to improve preservation quality. Interestingly, donor cardiomyocytes strongly expressed MR, which undergoes preservation-related phase separation. The phenomenon of macromolecular phase separation is not limited to the heart or MR during preservation. Cold preservation of the lung, liver and kidney also displays phase separation of other transcriptional regulators including histone deacetylase 1 (HDAC1), bromodomain-containing 4 (BRD4) and MR. Our results reveal an understudied area of preservation biology that may be further exploited to improve the preservation of multiple solid organs.