membrane leaflets facing the intermembrane space (IMS), which is crucial for remodeling. Tafazzin differs from phospholipases in that it contains a conserved histidine residue, His-77, as part of the conserved HX4D motif seen in acyltransferases. This motif is responsible for facilitating the Asp-His dyad mechanism seen in many serine proteases. Many unique forms of tafazzin have been identified, with lengths from 129 to 292 amino acids. Tafazzin has at least 4 different isoforms. It has a molecular weight around 35kDa but may also appear in lower molecular weights due to species differences in isoform expression. 7 functional classes of TAFAZZIN mutations have been classified based on the pathogenic loss-of-function mechanisms of each mutation. The TAFAZZIN gene contains two peptides independent of its active site for directing the protein to the mitochondria, forming residues 84–95 in exon 3 and residues 185–200 in exon 7/8 targets. Tafazzin localizes with peripheral association to membrane leaflets between the inner mitochondrial membrane (IMM) and outer mitochondrial membrane (OMM), facing the intermembrane space (IMS). Tafazzin's characteristic interfacial anchoring is achieved by its hydrophobic sequence from residues 215–232. Finally, the translocase of the outer membrane (TOM) and the translocase of the inner membrane (TIM) mediates tafazzin's movement and insertion into the OMM and anchoring to IMM. Function The TAFAZZIN gene provides instructions for producing a protein called tafazzin, which is localized to mitochondria, the energy-producing centers of cells. Tafazzin transacylase activity is responsible for cardiolipin remodeling, critical to maintaining mitochondrial inner membrane structure and function. It also has unique acyl specificity and membrane curvature sensing capabilities. Transacylase (remodeling) After its synthesis, cardiolipin cannot exert its proper functions until it is actively remodeled. Tafazzin, an acyl-specific transferase, catalyzes the acyl transfer reaction between phospholipids and lysophospholipids in a CoA-independent manner. The remodeling process of cardiolipin involves reaching a final acyl composition that is primarily linoleoyl residues. TAZ interacts with an immature cardiolipin by adding the fatty acid linoleic acid, which catalyzes the remodeling of the cardiolipin. The remodeling is achieved by transacylation or the deacylation-reacylation cycle. The deacylation-reacylation cycle, also known as the Lands cycle, begins with deacylation mediated by phospholipase Cld1 to form monolysocardiolipin (MLCL). MLCL is reacylated by tafazzin in a single-step reaction which transfers a linoleic acid group from phosphatidylcholine (PC), completing the CL deacylation-reacylation cycle. In contrast, transacylation involves the transfer of a linoleic acid group from phosphatidylcholine (PC) to MLCL. Such enzymatic activity