The mechanism of tafazzin, a key player in mitochondrial lipid metabolism

• Applicant: Professor Dr. Volker Zickermann
• Subject Area: Biochemistry ; Structural Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545208867

The phospholipid cardiolipin (CL) is an important component of mitochondrial membranes. When compared to other phospholipids, the discrepancy between a large hydrophobic body with four acyl chains and a small hydrophilic head group is remarkable and results in an overall conical shape of the CL molecule. The number of double bonds in the bound acyl chains is important for the physicochemical properties of CL. In order to adapt these properties to local needs and conditions, CL undergoes a remodeling process after its synthesis. First, a fatty acid residue is cleaved off by a phospholipase and mono-lyso-cardiolipin (MLCL) is formed. The acyltransferase tafazzin restores CL by transferring a fatty acid from a donor lipid to MLCL. Mutations in the tafazzin gene are known to cause Barth syndrome. This rare hereditary disease is characterized by pathological changes in the heart and skeletal muscles, as well as growth retardation and neutropenia. Barth syndrome was first described in 1983, but the link to the metabolism of CL was not elucidated until several years later. We have recently determined the first 3D structure of tafazzin and will now use this structural information to elucidate the molecular mechanism of the acyltransferase reaction. This will also contribute to a better understanding of Barth syndrome. My lab utilizes the aerobic yeast Yarrowia lipolytica as a model organism to elucidate the structure and function of mitochondrial enzyme complexes. We are particularly interested in respiratory complex, which plays a central role in aerobic energy metabolism. Complex I from Y. lipolytica consists of 43 subunits that have to be assembled during its biogenesis. We have shown that tafazzin in Y. lipolytica is part of an assembly intermediate of the membrane arm of complex I. In a human cell culture system used to study Barth syndrome, there is also an indication of a link between CL remodeling and the assembly of complex I. The second aim of this project is to better understand the functional link between tafazzin and the assembly of complex I. To achieve our two goals, we will combine biochemical and molecular biological techniques with electron microscopy, lipid analysis and molecular dynamics simulations.

• DFG Programme: Research Grants