Figure 3.

Schematic Representation of Cardiolipin (CL) Biosynthesis and Remodeling.

CL is synthesized in the inner mitochondrial membrane (IMM). Biosynthesis occurs within the matrix leaflet of the IMM, while the final remodeling step can be catalyzed by three different enzymes, including tafazzin (TAZ) in the intermembrane space (IMS)-facing leaflet, monolysocardiolipin acyltransferase 1 (MLCLAT1) on the matrix-leaflet of the IMM, and acyl-CoA:lysocardiolipin acyltransferase 1 (ALCAT1) on the endoplasmic reticulum (ER). Phosphatidic acid (PA) is transported from the ER to the IMM, where it is converted to CL via a series of enzymatic reactions. PG that is generated on the matrix-leaflet of the IMM is trafficked out of the mitochondrion (broken line) and remodeled by SERAC1 on the ER side. Remodeled PG may translocate back to the matrix leaflet of the IMM (broken line) to serve as substrate for CL synthesis. PA can also be dephosphorylated into diacylglycerol (DAG) by the phosphatase LIPIN1 in the outer mitochondrial membrane (OMM). DAG is then able to traffic across the OMM (broken line) and be phosphorylated by acylglycerol kinase (AGK), forming PA in the IMS-side of the IMM. Figure created with BioRender.com. Abbreviations: CLS1, CL synthase; MLCL, monolysocardiolipin; pCL, premature CL; PG, phosphatidylglycerol; PGP, phosphatidylglycerol phosphate; PGS1, phosphatidylglycerol phosphate synthase; PLA₂, phospholipase A₂; PRELID1, protein of relevant evolutionary and lymphoid interest domain; PTPMT1, protein-tyrosine phosphatase mitochondrial 1; SERAC1, serine active site containing 1; TAMM41, TAM41 translocator assembly and maintenance homolog; TRIAP1, TP53-regulated inhibitor of apoptosis 1.