Reduction of mitochondrial cardiolipin (CL) levels has postulated to directly compromise the function of several essential enzymes of the mitochondria. The resulting mitochondrial dysfunction compromises terminal oxidation that accentuates oxidative damage to tissue. This process has been observed in aging-related disease, ischemia/reperfusion that accentuates oxidative damage to tissue. This process has been observed in aging-related diseases, ischemia/reperfusion, that may be a contributing factor to Alzheimer's disease, apoptosis and cancer. There is limited genetic evidence for the critical roles with which CL has been associated complicated by the lack of mutants in the synthesis of CL in eukaryotic cells. The genes from Saccharomyces cerevisiae (CRD1 and PGS1) that encode the enzymes that synthesize CL and its precursor phosphatidylglycerol (PG), respectively, have been isolated by the sponsoring laboratory. Using these genes, the cellular processes dependent on CL will be identified using yeast as a model eukaryote. The laboratory has created a yeast strain in which expression of PGS1 is exogenously regulated. A CRD1 regulated expression strain as well as temperature sensitive mutants will be created for studies requiring rapid downshifts in enzymatic activity. Once these strains are characterized, a concerted effort will be placed on understanding the role PG and CL play in the import, assembly, and function of mitochondrial inner membrane protein complexes necessary for aerobic growth. The cytochrome oxidase complex will be specifically studied. The isolation and identification of second site suppressors will afford genetic insight into the function of these phospholipids Given the complexity of molecular genetic and biochemical studies in somatic cells into the function of these phospholipids. Given the complexity of molecular genetic and biochemical studies in somatic cells and the similarity of PG and CL synthesis and function in all eukaryotic cells, detailed studies of CL function in yeast will lead to a clearer understanding of the function of this phospholipid in the normal growth and metabolism of cells as well as the specific deficiencies of disease states involving CL reduction.
| Ostrander, D B; Zhang, M; Mileykovskaya, E et al. (2001) Lack of mitochondrial anionic phospholipids causes an inhibition of translation of protein components of the electron transport chain. A yeast genetic model system for the study of anionic phospholipid function in mitochondria. J Biol Chem 276:25262-72 |
| Ostrander, D B; Sparagna, G C; Amoscato, A A et al. (2001) Decreased cardiolipin synthesis corresponds with cytochrome c release in palmitate-induced cardiomyocyte apoptosis. J Biol Chem 276:38061-7 |
