Unveiling the last missing link of the cardiolipin synthetic pathway in mitochondria

electrochemical energy stored as a proton gradient across the mitochondrial inner membrane (IM). To generate the proton gradient, the respiratory-chain complexes in the IM pump up protons from the matrix to the inter-membrane space by coupling it to the electron transport through the respiratory chain. The efficient electron flow relies on the respiratory-chain super-complex formation, which is facilitated by the mitochondrial signature phospholipid cardiolipin (CL) [1]. CL directly interacts with the respiratory-chain complexes, mitochondrial carrier proteins including ADP/ATP carrier (AAC) etc. and stabilizes the super complexes consisting of Complexes I, III and IV in mammals and Complexes III and IV with AAC in yeast [1]. In addition, it is known that the assembly and maintenance of the TIM23 complex, a mitochondrial protein translocator in the IM, depends on the presence of CL [2]. Although the electron transport is essential for energy production in mitochondria, it could also generate reactive oxygen species (ROS), which are the potential cause of the oxidative damage of DNA and proteins as well as phospholipids in mitochondria. Accumulation of oxidative damage is thought to lead to mitochondrial and cellular dysfunction associated with aging [3]. CL is one of the main targets of ROS in mitochondria due to its IM location close to the sites of ROS production and its feature containing high-levels of unsaturated fatty acids [3]. Therefore CL could be a key molecule in aging process. CL is synthesized through several steps of modifications of phosphatidic acid (PA) in the IM and is remodeled by deacylation and re-acylation that generate mature CL with unsaturated fatty acids [1]. Despite its physiological importance, it was not clear how CL is synthesized in mitochondria. In particular, an enzyme responsible for the first step of the CL synthesis, i.e. generation of an important intermediate phospholipid, CDP-diacylglycerol (CDP-DAG), in mitochondria was not identified. Editorial Tam41 as a mitochondrial CDP-DAG synthase and the cellular system to compensate the loss of Tam41. Tam41 was originally identified as a protein important for assembly and maintenance of the TIM23 complex in the IM [4]. However, a subsequent study showed that loss of Tam41 leads to significant decrease in CL and accumulation of PA, the precursor phospholipid of CDP-DAG [5]. Besides, respiratory-chain super complexes tend to be destabilized in cells lacking Tam41, which indicates that the role of Tam41 is not limited to the TIM23 complex but to the protein complexes in the IM in …