The product of the open reading frame YPL206c, Pgc1p, of the yeast Saccharomyces cerevisiae displays homology to bacterial and mammalian glycerophosphodiester phosphodiesterases. Deletion of PGC1 causes an accumulation of the anionic phospholipid, phosphatidylglycerol (PG), especially under conditions of inositol limitation. This PG accumulation was not caused by increased production of phosphatidylglycerol phosphate or by decreased consumption of PG in the formation of cardiolipin, the end product of the pathway. PG accumulation in the pgc1⌬ strain was caused rather by inactivation of the PG degradation pathway. Our data demonstrate an existence of a novel regulatory mechanism in the cardiolipin biosynthetic pathway in which Pgc1p is required for the removal of excess PG via a phospholipase C-type degradation mechanism. Cardiolipin (CL)2 is a major mitochondrial anionic phospholipid with important functions in promoting cell growth, anaerobic metabolism, mitochondrial function, and biogenesis (1, 2). Phosphatidylglycerol is not only a metabolic precursor in the biosynthetic pathway leading to the formation of cardiolipin but itself is an important phospholipid; for example it is the sole phospholipid of thylakoid membranes of prokaryotic and eukaryotic oxygenic photosynthetic organisms (3). In mammals, PG is especially important in pulmonary surfactant, an essential fluid produced by alveolar type II cells that covers the entire surface of the lung (4). Considering the importance of this anionic phospholipid, little is known about the mechanisms by which eukaryotic cells control PG membrane composition.In yeast cells, PG is a low abundance phospholipid, present at best as a few tenths of a percent of total cellular phospholipids, even under the conditions of respiratory growth (5). Therefore, PG is considered to be mainly a metabolic precursor to CL. Biosynthesis of CL starts with common intermediates of phospholipid biosynthesis, phosphatidic acid and CDP-diacylglycerol (DAG) (Fig. 1). Phosphatidylglycerol phosphate (PGP) is formed from CDP-DAG and glycerol 3-phosphate. This step is catalyzed by PGP synthase, product of the PGS1/PEL1 gene (6, 7). PGP is subsequently dephosphorylated to form PG. Finally, CL is synthesized in yeast and other eukaryotic organisms from CDP-DAG and PG via a reaction catalyzed by cardiolipin synthase (CRD1) (5,8,9). It is important to note that both CL and PG are subject to intense remodeling subsequent to their de novo synthesis (10).Mitochondrial phospholipid biosynthetic activities in general respond to factors affecting mitochondrial development and function, such as carbon source, growth phase, availability of oxygen, and mutations affecting mitochondrial development and function (11,12). In fact, both enzymatic activities of the CL biosynthetic pathway, PGP synthase and CL synthase, respond to mitochondrial development factors in such a way as to increase the production of CL when cells switch from fermentative to respiratory growth (13-15). A typical feature of yeast phosphol...
Cardiolipin and its precursor phosphatidylglycerol are two anionic phospholipids that are essential for the biogenesis of functional mitochondria. To assess their role in mitochondrial and cellular functions in the pathogenic yeast Candida glabrata, a functional characterization of the CgPGS1 gene encoding the phosphatidylglycerolphosphate synthase has been carried out. Transposon insertion mutation in CgPGS1 resulted in the loss of phosphatidylglycerolphosphate synthase activity and in deficiency of both phosphatidylglycerol and cardiolipin. The Cgpgs1 Delta mutant cells displayed reduced amounts of cytochrome b and cytochrome a, and had impaired growth on minimal media containing non-fermentable carbon and energy sources. They did not grow at elevated temperatures and failed to form colonies after induction of mitochondrial DNA deletions. The mutant cells also displayed a decreased susceptibility to fluconazole, ketoconazole, clotrimazole, voriconazole and posaconazole. In the Cgpgs1 Delta mutant, a quantitative real time PCR revealed enhanced mRNA levels for multidrug resistance associated genes such as CgPDR1 encoding transcriptional activator and CgCDR1, CgPDH1 and CgSNQ2 coding for drug efflux transporters. These results indicate that CgPGS1 and anionic phospholipids are required for optimal mitochondrial functions and maintenance of yeast susceptibility to azole antifungals.
The petite-negative yeast Kluyveromyces lactis does not tolerate the loss of phosphatidylglycerol (PG). We demonstrate that the lethality of PG loss is suppressed in strains carrying a mutation in the beta subunit of F(1) ATPase (mgi1-1). Phenotypic characterization shows that the strain lacking the phosphatidylglycerolphosphate synthase gene (KlPGS1) is able to grow only on glucose, but significantly more slowly and to substantially lower densities than the parental mgi1-1 strain. In addition, oxygen consumption in the DeltaKlpgs1 strain is <1% of the parental strain. Western blot analysis of mitochondrial membrane proteins shows that the amounts of some proteins are substantially decreased or even not detectable in this mutant. However, overexpression of the KlPGS1 gene under the inducible GAL1 promoter does not restore the ability of DeltaKlpgs1 cells to grow on galactose, indicating the presence of some other mutations and/or deletions in genes involved in oxidative phosphorylation. We also demonstrate that DeltaKlpgs1 cells do not spontaneously lose mtDNA, but are able to survive its loss after ethidium bromide mutagenesis. Deletion of the cardiolipin synthase gene (KlCLS1) in mgi1-1 has only a minimal effect on mitochondrial physiology, and additional experiments show that this deletion is also viable in wild-type K. lactis.
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