Cardiolipin Content of Wild Type and Mutant Yeasts in Relation to Mitochondrial Function and Development

Jakovcic, Smilja; Getz, Godfrey S.; Rabinowitz, Murray; Jakob, H; Swift, Hewson

doi:10.1083/jcb.48.3.490

Cited by 91 publications

(59 citation statements)

References 22 publications

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“…To resolve this discrepancy, phospholipid analyses were carried out at different growth phases in two different crd1⌬ strains by using a sensitive radiolabeling approach. CL and PG levels increased by Ͼ2-fold from the early logarithmic to the late stationary phase in YPD medium (Table II), whereas in YPGE medium the levels remained constantly high (Table III), which is consistent with previous reports (22,26). PG levels in crd1⌬ cells were comparable with wild type levels of CL plus PG.…”

Section: Uncoupled Oxidative Phosphorylation In Crd1⌬supporting

confidence: 81%

“…In all the above studies, measurements were taken at a single point in the growth phase. However, growth phase is known to regulate phospholipid levels (26). This effect is specifically important for mitochondrial phospholipids (PG and CL), as mitochondrial development is subject to glucosemediated repression, resulting in reduced mitochondria-specific phospholipids (22,26,27).…”

Section: Uncoupled Oxidative Phosphorylation In Crd1⌬mentioning

confidence: 99%

“…However, growth phase is known to regulate phospholipid levels (26). This effect is specifically important for mitochondrial phospholipids (PG and CL), as mitochondrial development is subject to glucosemediated repression, resulting in reduced mitochondria-specific phospholipids (22,26,27). To resolve this discrepancy, phospholipid analyses were carried out at different growth phases in two different crd1⌬ strains by using a sensitive radiolabeling approach.…”

Section: Uncoupled Oxidative Phosphorylation In Crd1⌬mentioning

confidence: 99%

See 2 more Smart Citations

Absence of Cardiolipin Results in Temperature Sensitivity, Respiratory Defects, and Mitochondrial DNA Instability Independent of pet56

Zhong¹,

Gohil²,

Ma³

et al. 2004

Journal of Biological Chemistry

101

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Cardiolipin (CL) is a dimeric phospholipid localized primarily in the mitochondrial membrane. Previous studies have shown that yeast cells containing a disruption of CRD1, the structural gene encoding CL synthase, exhibit temperature-sensitive colony formation and multiple mitochondrial defects. A recent report (Zhang, M., Su, X., Mileykovskaya, E., Amoscato, A. A., and Dowhan, W. (2003) J. Biol. Chem. 278, 35204 -35210) suggested that defects associated with CL deficiency may result from the reduced expression of PET56 in crd1⌬ mutant backgrounds and should be reevaluated. In the current study, we present evidence that CL deficiency leads to mitochondrial DNA instability, loss of viability, and defects in oxidative phosphorylation at elevated temperatures. The observed mutant phenotypes are characteristic of crd1⌬ mutant cells of both PET56 and pet56 backgrounds and are complemented by an episomal copy of CRD1 but not by expression of the PET56 gene. Phosphatidylglycerol is elevated in crd1⌬ mutant cells when grown in the presence of fermentable and non-fermentable carbon sources, although the extent of the increase is higher in nonfermentable medium. An increase in the ratio of phosphatidylethanolamine to phosphatidylcholine was also apparent in the mutant. These findings demonstrate that CRD1, independent of PET56, is required for optimal mitochondrial function and for an essential cellular function at elevated temperatures.Cardiolipin (CL), 1 a unique phospholipid with dimeric structure, is ubiquitous in eukaryotes and is primarily found in the mitochondrial inner membrane (1). It plays a key role in mitochondrial bioenergetics by optimizing the activities of enzymes in the oxidative phosphorylation pathway (1), stabilizing the supercomplexes of Saccharomyces cerevisiae respiratory chain complexes III and IV (2), preventing rate-dependent uncoupling, and providing osmotic stability in yeast mitochondria (3). CL is also involved in mitochondrial biogenesis, possibly via assisting protein import into mitochondria (4) and maintaining optimal mitochondrial internal structure (5). Defective remodeling of CL is associated with Barth syndrome, a severe genetic disorder characterized by cardiomyopathy, neutropenia, skeletal myopathy, and respiratory chain defects (6). The phenotype of Barth syndrome is dependent upon multiple factors that are not well understood (7,8). Elucidation of the functions of CL will help to clarify the abnormalities associated with this disorder.We have observed that the yeast crd1⌬ mutant, which lacks CL synthase and has no detectable CL, loses cell viability during growth at elevated temperatures (4, 9). Crd1⌬ mutant cells cannot form colonies at 37°C from single cells seeded on YPD (1% yeast extract, 2% peptone, and 2% dextrose) plates (9). In addition, crd1⌬ mutant cells grown in fermentable or non-fermentable carbon sources also segregate large numbers of petites (respiratory incompetent cells) after prolonged culture at elevated temperatures (4). CL is, thus, essential for maintaining...

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Section: Uncoupled Oxidative Phosphorylation In Crd1⌬supporting

confidence: 81%

Section: Uncoupled Oxidative Phosphorylation In Crd1⌬mentioning

confidence: 99%

Section: Uncoupled Oxidative Phosphorylation In Crd1⌬mentioning

confidence: 99%

See 1 more Smart Citation

Absence of Cardiolipin Results in Temperature Sensitivity, Respiratory Defects, and Mitochondrial DNA Instability Independent of pet56

Zhong¹,

Gohil²,

Ma³

et al. 2004

Journal of Biological Chemistry

101

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“…An early study by Jakovcic et al (38) shows that CL levels were correlated with mitochondrial development. CL was more abundant in the stationary than logarithmic growth phase and in aerobic versus anaerobic conditions.…”

Section: Cardiolipin (Cl)mentioning

confidence: 99%

Cardiolipin Biosynthesis and Mitochondrial Respiratory Chain Function Are Interdependent

Gohil

Hayes

Matsuyama

et al. 2004

Journal of Biological Chemistry

131

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Cardiolipin (CL) is an acidic phospholipid present almost exclusively in membranes harboring respiratory chain complexes. We have previously shown that, in Saccharomyces cerevisiae, CL provides stability to respiratory chain supercomplexes and CL synthase enzyme activity is reduced in several respiratory complex assembly mutants. In the current study, we investigated the interdependence of the mitochondrial respiratory chain and CL biosynthesis. Pulse-labeling experiments showed that in vivo CL biosynthesis was reduced in respiratory complexes III (ubiquinol:cytochrome c oxidoreductase) and IV (cytochrome c oxidase) and oxidative phosphorylation complex V (ATP synthase) assembly mutants. CL synthesis was decreased in the presence of CCCP, an inhibitor of oxidative phosphorylation that reduces the pH gradient but not by valinomycin or oligomycin, both of which reduce the membrane potential and inhibit ATP synthase, respectively. The inhibitors had no effect on phosphatidylglycerol biosynthesis or CRD1 gene expression. These results are consistent with the hypothesis that in vivo CL biosynthesis is regulated at the level of CL synthase activity by the ⌬pH component of the proton-motive force generated by the functional electron transport chain. This is the first report of regulation of phospholipid biosynthesis by alteration of subcellular compartment pH. Cardiolipin (CL)1 is an acidic glycerophospholipid with a unique dimeric structure consisting of four fatty acyl chains (1). It is almost exclusively present in membranes designed to generate an electrochemical potential gradient for ATP synthesis, including the mitochondrial inner membrane and bacterial plasma membrane. CL plays a vital role in mitochondrial structure and function by providing osmotic stability to mitochondrial membranes (2) and by specifically interacting with many inner membrane proteins (reviewed in Refs. 3 and 4). Normal levels of CL are required for optimal mitochondrial bioenergetic functions (5, 6). Decreased CL levels are observed in cells undergoing apoptosis (7-9) and aging (10, 11) and in fibroblasts of Barth syndrome patients (12). Thus, a detailed understanding of the regulation of CL levels will provide important insights into the manifestation of these conditions. CL is associated with major proteins of the mitochondrial respiratory chain including NADH dehydrogenase (complex I) (13), ubiquinol:cytochrome c reductase (complex III) (13-17), and cytochrome c oxidase (complex IV) (18, 19), the ATP synthase (complex V) (20), and the carrier proteins for phosphate (21) and adenine nucleotides (22). CL modulates the catalytic activities of proteins, as seen in the case of the ADP-ATP carrier (5, 23, 24) and complex IV (25), and/or provides stability as reported for complex III (17) and complex IV (19). CL binds specifically and irreversibly to cytochrome c (26), providing a membrane attachment site for cytochrome c and limiting the soluble pool of the protein. X-ray crystallography studies have further confirmed the specific interaction...

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“…The lipid component of the yeast ER membrane consists largely of phosphatidylcholine and phosphatidylinositol (Jakovcic et al, 1971). The rate-limiting step in inositol phospholipid biosynthesis is carried out by the INO1 gene prod-uct.…”

Section: Introductionmentioning

confidence: 99%

IN02, A Positive Regulator of Lipid Biosynthesis, Is Essential for the Formation of Inducible Membranes in Yeast

Block-Alper

Webster

Zhou

et al. 2002

MBoC

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Expression of the 180-kDa canine ribosome receptor inSaccharomyces cerevisiae leads to the accumulation of ER-like membranes. Gene expression patterns in strains expressing various forms of p180, each of which gives rise to unique membrane morphologies, were surveyed by microarray analysis. Several genes whose products regulate phospholipid biosynthesis were determined by Northern blotting to be differentially expressed in all strains that undergo membrane proliferation. Of these, the INO2 gene product was found to be essential for formation of p180-inducible membranes. Expression of p180 in ino2Δ cells failed to give rise to the p180-induced membrane proliferation seen in wild-type cells, whereas p180 expression in ino4Δ cells gave rise to membranes indistinguishable from wild type. Thus, Ino2p is required for the formation of p180-induced membranes and, in this case, appears to be functional in the absence of its putative binding partner, Ino4p.

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Cardiolipin Content of Wild Type and Mutant Yeasts in Relation to Mitochondrial Function and Development

Cited by 91 publications

References 22 publications

Absence of Cardiolipin Results in Temperature Sensitivity, Respiratory Defects, and Mitochondrial DNA Instability Independent of pet56

Absence of Cardiolipin Results in Temperature Sensitivity, Respiratory Defects, and Mitochondrial DNA Instability Independent of pet56

Cardiolipin Biosynthesis and Mitochondrial Respiratory Chain Function Are Interdependent

IN02, A Positive Regulator of Lipid Biosynthesis, Is Essential for the Formation of Inducible Membranes in Yeast

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