Mieap forms membraneless organelles to compartmentalize and facilitate cardiolipin metabolism

Abstract Biomolecular condensates function as membraneless organelles that compartmentalize and facilitate efficient biological reactions. They are formed by proteins with intrinsically disordered regions (IDRs) via liquid–liquid phase separation. Mieap/SPATA18, a p53-inducible protein, participates in suppression of colorectal tumors by promoting mitochondrial quality control. However, the regulatory mechanism involved remains unclear. Here, we report that Mieap is an IDR-containing protein that drives formation of biomolecular condensates in mitochondria. Mieap biomolecular condensates specifically phase separate the mitochondrial phospholipid, cardiolipin. Lipidomic analysis of cardiolipin suggests that Mieap promotes enzymatic reactions involved in cardiolipin metabolism, including biosynthesis and remodeling. Accordingly, four cardiolipin biosynthetic enzymes, TAMM41, PGS1, PTPMT1, and CRLS1, and two remodeling enzymes, PLA2G6 and TAZ, are phase-separated by Mieap biomolecular condensates. Mieap-deficient mice exhibit altered crista structure in mitochondria of various tissues, including brown fat, and tend to become obese. These results suggest that Mieap drives formation of membraneless organelles to compartmentalize and promote cardiolipin metabolism at the inner mitochondrial membrane, thus potentially contributing to mitochondrial quality control.