The role of mitochondrial anionic phospholipids in signaling pathways and essential functions.

摘要

Cardiolipin (CL) is the signature phospholipid of the mitochondria. It plays an important role in mitochondrial bioenergetics and biogenesis. In addition, CL is important for essential cellular processes. The importance of CL is underscored by the finding that aberrant CL metabolism is associated with a severe genetic disorder, Barth syndrome (BTHS). Elucidation of the function of CL will help to clarify the pathological mechanisms underlying BTHS and the treatment of this disorder.; Pgs1p and Crd1p catalyze the committed and final steps of CL synthesis in yeast Saccharomyces cerevisiae, respectively. The pgs1Delta and crd1Delta null mutants were used in this study. A previous study showed that pgs1Delta cells exhibit severe growth and cell wall defects. The data presented here indicate that the defective cell wall in pgs1Delta is attributed to defects in glucan synthesis and the cell integrity pathway. Intriguing findings by others suggest that PG activates a protein kinase C (PKC) isoform in mammalian cells. Therefore, we hypothesized that PG compensates for CL to activate the cell wall pathway. Consistent with this hypothesis,the crd1Delta mutant does not exhibit cell wall defects. PKC activation, measured by dual phosphorylation of Slt2p (the downstream effector of the cell integrity pathway) is defective in the pgs1Delta mutant but not in crd1Delta. In addition, altered expression of SUC2 and TCM1, hallmarks of PKC1 deficient cells, was observed in pgs1Delta but not in crd1Delta. Therefore, PG may compensate for CL for cell wall biogenesis by activating PKC-mediated Slt2p phosphorylation.; To further elucidate CL function in the crd1Delta mutant, genetic screens for mutants synthetically lethal with crd1Delta were carried out. Synthetic lethal interactions are indicative of shared functions or direct interactions between the mutants. A classic genetic screen and a synthetic genetic array (SGA) screen were carried out, which identified putative mutants involved in several essential cellular processes, including cellular processes not previously associated with CL. Analysis of these synthetic lethal interactions is expected to contribute to our understanding of the role of CL in essential cellular processes, and of how perturbation of these interactions may lead to human diseases such as BTHS.