Studies of the cardiolipin interactome

Cardiolipin (CL) is a unique phospholipid that is fundamental to the structure and function of the highly curved cristae membranes of mitochondria. Given its distinctive cone-shaped molecular architecture, CL induces negative membrane curvature in a bilayer setting. Another key feature of CL is its intrinsic ability to interact with various ligands, including cytochrome c, the anti-neoplastic anthracycline, doxorubicin, and the divalent cation, calcium. Although these, and other, binding interactions exert profound effects on mitochondrial and cellular function, they are difficult to study in intact mitochondria. Whereas liposomes provide a potential model membrane system, their relatively large size, limited ability to accommodate CL and the presence of an inaccessible interior bilayer leaflet, make these structures suboptimal. The discovery that CL can be formulated into aqueous soluble, reconstituted high density lipoprotein particles, termed nanodisks (ND), provides an alternative model membrane system. Comprised solely of CL and an apolipoprotein scaffold, CL-ND exist as a disk-shaped phospholipid bilayer whose perimeter is stabilized by contact with the scaffold protein. In these nanoscale particles, both leaflets of the bilayer are solvent accessible, an advantage for studies of ligand interactions. Recent experiments employing CL-ND have yielded novel insight into apoptosis, cardiotoxicity and CL-dependent bilayer to non-bilayer transitions.