The topology and regulation of cardiolipin biosynthesis and remodeling in yeast

Baile, Matthew G.; Lu, Ya Wen; Claypool, Steven M.

doi:10.1016/j.chemphyslip.2013.10.008

Cited by 51 publications

(44 citation statements)

References 95 publications

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“…We hypothesize that this limited accessibility of the Crd1p-specific PG fraction reflects a different subcellular localization of the Crd1p and Pgc1p enzymes. Crd1p activity has been localized to the matrix side of the IMM [55,56]. In the frame of the proposed model, we expect the Crd1p-specific pool of PG to localize there, too.…”

Section: Discussionmentioning

confidence: 89%

Specific degradation of phosphatidylglycerol is necessary for proper mitochondrial morphology and function

Pokorná

C̆ermáková

Horváth

et al. 2016

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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In yeast, phosphatidylglycerol (PG) is a minor phospholipid under standard conditions; it can be utilized for cardiolipin (CL) biosynthesis by CL synthase, Crd1p, or alternatively degraded by the phospholipase Pgc1p. The Saccharomyces cerevisiae deletion mutants crd1Δ and pgc1Δ both accumulate PG. Based on analyses of the phospholipid content of pgc1Δ and crd1Δ yeast, we revealed that in yeast mitochondria, two separate pools of PG are present, which differ in their fatty acid composition and accessibility for Pgc1p-catalyzed degradation. In contrast to CL-deficient crd1Δ yeast, the pgc1Δ mutant contains normal levels of CL. This makes the pgc1Δ strain a suitable model to study the effect of accumulation of PG per se. Using fluorescence microscopy, we show that accumulation of PG with normal levels of CL resulted in increased fragmentation of mitochondria, while in the absence of CL, accumulation of PG led to the formation of large mitochondrial sheets. We also show that pgc1Δ mitochondria exhibited increased respiration rates due to increased activity of cytochrome c oxidase. Taken together, our results indicate that not only a lack of anionic phospholipids, but also excess PG, or unbalanced ratios of anionic phospholipids in mitochondrial membranes, have harmful consequences on mitochondrial morphology and function.

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Section: Discussionmentioning

confidence: 89%

Specific degradation of phosphatidylglycerol is necessary for proper mitochondrial morphology and function

Pokorná

C̆ermáková

Horváth

et al. 2016

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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“…Thus, the opi1⌬ mutant shares no reported metabolic or regulatory phenotype with scs2⌬ other than low CL levels. To support CL biosynthesis, PA synthesized in the ER must be transferred to the outer mitochondrial membrane and transferred to the inner mitochondrial membrane to be converted to CDP-DAG by Tam41p, the mitochondrial CDP-DAG synthase (35,53,54) (Fig. 1).…”

Section: Discussionmentioning

confidence: 99%

“…PA used in the synthesis of CDP-DAG in the inner mitochondrial membrane is synthesized in the ER and must be transferred to the outer mitochondrial membrane (53-55) (Fig. 1), primarily via the ERMES (35)(36)(37)(38). From the outer mitochondrial membrane, PA must be transferred to the inner mitochondrial membrane by a process requiring the Ups1p-Mdm35 complex (36,53,56).…”

Section: Levels Are Significantly Reduced In the Opi1mentioning

confidence: 99%

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Interaction between repressor Opi1p and ER membrane protein Scs2p facilitates transit of phosphatidic acid from the ER to mitochondria and is essential for INO1 gene expression in the presence of choline

Gaspar¹,

Chang²,

Jesch

et al. 2017

Journal of Biological Chemistry

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In the yeast Saccharomyces cerevisiae, the Opi1p repressor controls the expression of INO1 via the Opi1p/Ino2p-Ino4p regulatory circuit. Inositol depletion favors Opi1p interaction with both Scs2p and phosphatidic acid at the endoplasmic reticulum (ER) membrane. Inositol supplementation, however, favors the translocation of Opi1p from the ER into the nucleus, where it interacts with the Ino2p-Ino4p complex, attenuating transcription of INO1. A strain devoid of Scs2p (scs2⌬) and a mutant, OPI1FFAT, lacking the ability to interact with Scs2p were utilized to examine the specific role(s) of the Opi1p-Scs2p interaction in the regulation of INO1 expression and overall lipid metabolism. Loss of the Opi1p-Scs2p interaction reduced INO1 expression and conferred inositol auxotrophy. Moreover, inositol depletion in strains lacking this interaction resulted in Opi1p being localized to sites of lipid droplet formation, coincident with increased synthesis of triacylglycerol. Supplementation of choline to inositol-depleted growth medium led to decreased TAG synthesis in all three strains. However, in strains lacking the Opi1p-Scs2p interaction, Opi1p remained in the nucleus, preventing expression of INO1. These data support the conclusion that a specific pool of phosphatidic acid, associated with lipid droplet formation in the perinuclear ER, is responsible for the initial rapid exit of Opi1p from the nucleus to the ER and is required for INO1 expression in the presence of choline. Moreover, the mitochondria-specific phospholipid, cardiolipin, was significantly reduced in both strains compromised for Opi1p-Scs2p interaction, indicating that this interaction is required for the transfer of phosphatidic acid from the ER to the mitochondria for cardiolipin synthesis.

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“…On other hand, in the eukaryotic pathway, glycerol 3-phosphate is transferred to a CDP-DAG molecule to produce PGP, as in bacteria. However, after dephosphorylation of PGP, PG is condensed to another CDP-DAG molecule producing CL, thus differing in this step in the bacterial substrates used for synthesis [7]. As stated before, the enzymatic mechanisms differ between domains: in bacteria, the first enzyme, phosphatidylglycerol phosphate synthase (Pgs T ), belong to the transferase class (E.C.…”

Section: Introductionmentioning

confidence: 97%

The chimeric origin of the cardiolipin biosynthetic pathway in the Eukarya domain

Luévano‐Martínez¹

2015

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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Cardiolipin (CL) and phosphatidylglycerol (PG) are the main anionic phospholipids present in the Eukarya and Bacteria domains. They participate in energy transduction by activating and stabilizing the components of the oxidative phosphorylation machinery. Experimental evidence shows that they are synthesized by two different mechanisms which indicate that both pathways evolved convergently. Former studies on the lipid composition of archaeal membranes showed the absence of CL in these organisms, consequently, restricting it to the Eukarya and Bacteria domains. Interestingly, recent studies have demonstrated that both CL and PG are present as constitutive components of membranes of the haloarchaea group. However, this scenario complicates the analysis of the evolutionary origin of this biosynthetic pathway. Here I suggest that a phospholipid biosynthetic pathway in Eukarya probably arose from a chimeric event between bacterial and archaeal enzymes during the endosymbiosis event. Phylogenetic analyses support the different evolutionary origin of the enzymes comprising this pathway in bacteria and Eukarya. Based on protein domain analyses, orthologous proteins in the Archaea domain were identified. An integrative analysis of the proteins found demonstrates that CL biosynthesis in major clades of the Eukarya domain originated by chimerism between the bacteria and archaea pathways. Moreover, primary and secondary endosymbiontic events in plants and chromoalveolata respectively, reshaped this pathway again. The implications and advantages that these new enzymatic orders conferred to the Eukarya domain are discussed.

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The topology and regulation of cardiolipin biosynthesis and remodeling in yeast

Cited by 51 publications

References 95 publications

Specific degradation of phosphatidylglycerol is necessary for proper mitochondrial morphology and function

Specific degradation of phosphatidylglycerol is necessary for proper mitochondrial morphology and function

Interaction between repressor Opi1p and ER membrane protein Scs2p facilitates transit of phosphatidic acid from the ER to mitochondria and is essential for INO1 gene expression in the presence of choline

The chimeric origin of the cardiolipin biosynthetic pathway in the Eukarya domain

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