Principles of Biochemistry/Lipids/Cardiolipin



Cardiolipin, the signature phospholipid of mitochondria, is a lipid dimer. The structure consists of two phosphatidyl groups bridged by a glycerol. The four acyl chains distinguish it from typical phospholipids which have two acyl chains. It is synthesized in the inner membrane of the mitochondria complex. In contrast with other phospholipids, cardiolipin remains firmly associated with mitochondrial membranes.

Synthesis
In eukaryotic cells, cardiolipin synthesis takes places in the mitochondrion. Key steps such as the dephosphorylation of phosphatidylglycerolphosphate and the initiation of the cardiolipin remodeling cascade were identified to be linked with enzymatic activity. The biosynthesis begins with phospahtidylglycerolphosphate synthase (Pgs1) catylyzing the first step of the reaction producing phosphatidylglycerolphophate (PGP) from the condensation of cytidine 5'diphosphate-diacylglycerol (CDP-DAG) and glycerol-3-phosphate (G3P). PGP is then dephosphorylated to phosphatidylglycerol (PG)by a phosphatase identified as Gep4 and PTPMT1. Gep4 was identified in yeast for genetic interactors of prohibitins. PTPMT1 was discovered in mice. Next, cardiolipin synthase forms an immature cardiolipin from PG and CDP-DAG characterized by a random assortment of attached acyl chains that vary in length. The final phase of cardiolipid synthesis is acyl chain remodeling defined by the symmetric incorporation of unsaturated longer fatty acyl chains. The remodeling is initiated by a phospholipase specific to the organism. In yeast, the phospholipase is cardiolipin deacylase (Cld1) and in mammals the calcium-independent iPLA2γ. The phospholipase removes an acyl chain from the immature cardiolipin generating the intermediate, monolysocardiolipin (MLCL). The regeneration of cardiolipin from MLCL involves three different enzymes, tafazzin (Taz1), monolysocardiolipin acyltransferase 1 (MLCLAT1), and acyl-Coa:lysocardiollipin acyltransferase-1 (ALCAT1). MLCLAT1 and ALCAT1 utilize acyl-CoA as an acyl chain donor for the reacylation of MLCL. Taz1 is a transacylase that takes an acyl chain from another phospholipid, preferably phosphatidylcholine (PC) and adds it to MLCL. Each of these remodeling enzymes resides in a specific subcellular compartments for distinct functions. Taz1 and MLCLAT1 remodeling generates the mature cardiolipin while ALCAT1 remodeling produces the "bad" cardiolipin associated with pathologic processes.

Functions
Cardiolipin is the center of mitochondrial physiology. It plays a major role in the organization of the protein components of oxidative phosphorylation (OXPHOS). It improves the efficiency and adaptability of the OXPHOS machinery by two mechanisms. First, cardiolipin stabilizes higher order respiratory complexes. This increases the efficiency of electron flow and ADP/ATP exchange. In addition, cardiolipin acts as a protein trap to restrict the flow of electrons. Without cardiolipin, the functionality of the electron transport chain is reduced resulting in a weaker electrochemical gradient (ΔΨ).