Cardiolipin Stabilizes Respiratory Chain Supercomplexes

Pfeiffer, Kathy; Gohil, Vishal M.; Stuart, Rosemary A.; Hunte, Carola; Brandt, Ulrich; Greenberg, Miriam L.; Schägger, Hermann

doi:10.1074/jbc.m308366200

Cited by 728 publications

(640 citation statements)

References 55 publications

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“…Moreover, CL is required to fully reconstitute the activity of respiratory complex IV and the ADP/ATP carrier (AAC) in vitro (Hoffmann et al, 1994;Sedlak and Robinson, 1999). In organello, CL acts as a glue that stabilizes the assembly of individual respiratory complexes into so-called respiratory supercomplexes (Zhang et al, 2002(Zhang et al, , 2005Pfeiffer et al, 2003) that function to increase the efficiency of oxidative phosphorylation (Boumans et al, 1998;Zhang et al, 2005). Which aspect of CL (e.g., its two phosphate headgroups or four associated acyl chains) is responsible for these unique functional properties of CL is at present unknown.…”

Section: Introductionmentioning

confidence: 99%

The Cardiolipin Transacylase, Tafazzin, Associates with Two Distinct Respiratory Components Providing Insight into Barth Syndrome

Claypool¹,

Boontheung²,

McCaffery

et al. 2008

MBoC

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Mutations in the mitochondrial cardiolipin (CL) transacylase, tafazzin (Taz1p), result in the X-linked cardioskeletal myopathy, Barth syndrome (BTHS). The mitochondria of BTHS patients exhibit variable respiratory defects and abnormal cristae ultrastructure. The biochemical basis for these observations is unknown. In the absence of its target phospholipid, CL, a very large Taz1p complex is missing, whereas several discrete smaller complexes are still observed. None of the identified Taz1p complexes represents Taz1p homodimers. Instead, yeast Taz1p physically assembles in several protein complexes of distinct size and composition. The ATP synthase and AAC2, both required for oxidative phosphorylation, are identified in separate stable Taz1p complexes. In the absence of CL, each interaction is still detected albeit in reduced abundance compared with when CL is present. Taz1p is not necessary for the normal expression of AAC2 or ATP synthase subunits or assembly of their respective complexes. In contrast, the largest Taz1p complex requires assembled ATP synthase and CL. Mitochondria in ⌬taz1 yeast, similar to ATP synthase oligomer mutants, exhibit altered cristae morphology even though ATP synthase oligomer formation is unaffected. Thus, the Taz1p interactome defined here provides novel insight into the variable respiratory defects and morphological abnormalities observed in mitochondria of BTHS patients.

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Section: Introductionmentioning

confidence: 99%

The Cardiolipin Transacylase, Tafazzin, Associates with Two Distinct Respiratory Components Providing Insight into Barth Syndrome

Claypool¹,

Boontheung²,

McCaffery

et al. 2008

MBoC

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“…Cardiolipin is primarily found in the mitochondrial membranes of eukaryotes (Hoch, 1992) and the bacterial cytoplasmic membrane. Although the molecular function of cardiolipin is still unclear, several studies have suggested that it is required for the proper function of some proteins and protein complexes in the inner mitochondrial membrane (Hoch, 1992;Jiang et al, 2000;Pfeiffer et al, 2003;Palsdottir and Hunte, 2004;Zhang et al, 2005). Two functions have been proposed for cardiolipin: 1) participation in stabilization of the physical properties of the membrane Koshkin and Greenberg, 2002;Ma et al, 2004), for example, membrane fluidity and osmotic stability and 2) participation in protein function via direct interaction with membrane proteins Palsdottir and Hunte, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…When yeast cells are deleted for the CRD1 gene (cardiolipin synthase) cardiolipin is not synthesized and dissociation of the respiratory chain supercomplexes and oligomers of AAC is observed (Jiang et al, 2000;Zhang et al, 2002Zhang et al, , 2005. The reduced stability of these protein complex oligomers reflects the complete loss of cardiolipin from the mitochondrial membranes (Pfeiffer et al, 2003). In contrast to crd1⌬, yeast taz1⌬ mutant mitochondria still possess cardiolipin, although in reduced amounts and with altered structure (Vaz et al, 2003;Gu et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Taz1, an Outer Mitochondrial Membrane Protein, Affects Stability and Assembly of Inner Membrane Protein Complexes: Implications for Barth Syndrome

Brandner

Mick

Frazier

et al. 2005

MBoC

188

150

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The Saccharomyces cerevisiae Taz1 protein is the orthologue of human Tafazzin, a protein that when inactive causes Barth Syndrome (BTHS), a severe inherited X-linked disease. Taz1 is a mitochondrial acyltransferase involved in the remodeling of cardiolipin. We show that Taz1 is an outer mitochondrial membrane protein exposed to the intermembrane space (IMS). Transport of Taz1 into mitochondria depends on the receptor Tom5 of the translocase of the outer membrane (TOM complex) and the small Tim proteins of the IMS, but is independent of the sorting and assembly complex (SAM). TAZ1 deletion in yeast leads to growth defects on nonfermentable carbon sources, indicative of a defect in respiration. Because cardiolipin has been proposed to stabilize supercomplexes of the respiratory chain complexes III and IV, we assess supercomplexes in taz1⌬ mitochondria and show that these are destabilized in taz1⌬ mitochondria. This leads to a selective release of a complex IV monomer from the III 2 IV 2 supercomplex. In addition, assembly analyses of newly imported subunits into complex IV show that incorporation of the complex IV monomer into supercomplexes is affected in taz1⌬ mitochondria. We conclude that inactivation of Taz1 affects both assembly and stability of respiratory chain complexes in the inner membrane of mitochondria. INTRODUCTIONBarth Syndrome is an X-linked recessive disorder that is characterized by cardioskeletal myopathy, neutropenia, increased urine levels of 3-methylglutaconic acid, abnormal mitochondria, and respiratory chain dysfunction (Barth et al., 1983(Barth et al., , 1996Kelley et al., 1991;D'Adamo et al., 1997). The disease is often fatal in infancy and early childhood because of cardiac failure and bacterial infections (Barth et al., 2004). Bione et al. (1996) identified the gene responsible, termed Tafazzin (TAZ), and localized it to region q28 on the X chromosome. Sequence analyses demonstrate that the Taz protein is highly conserved from yeast to man and that it displays sequence similarity to acyltransferases that participate in the metabolism of phospholipids (Neuwald, 1997). Phospholipid analyses of fibroblasts from patients and yeast taz1⌬ mutant cells show reduced cardiolipin levels and an altered acyl chain composition (Vreken et al., 2000;Vaz et al., 2003;Xu et al., 2003;Gu et al., 2004).Cardiolipin is formed by two glycerol-linked phosphatidyl moieties. The four acyl side chains are usually monoand di-unsaturated fatty acids in higher eukaryotes. Remodeling of cardiolipin through a cycle of deacylation and successive reacylation leads to the final and specific acyl composition. In heart and skeletal muscle mitochondria the tetralinoleoyl species predominates Xu et al., 2003;Hatch, 2004). Cardiolipin is primarily found in the mitochondrial membranes of eukaryotes (Hoch, 1992) and the bacterial cytoplasmic membrane. Although the molecular function of cardiolipin is still unclear, several studies have suggested that it is required for the proper function of some proteins and protein complexe...

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“…CL plays a key role in mitochondrial bioenergetics (Jiang et al, 2000; Greenberg, 2000, 2002;Schlame et al, 2000;Pfeiffer et al, 2003) and is also involved in mitochondrial biogenesis (Kawasaki et al, 1999;Jiang et al, 2000). Defective remodeling of CL is associated with Barth syndrome, a severe genetic disorder characterized by cardiomyopathy, neutropenia, skeletal myopathy, and respiratory chain defects (Vreken et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Disruption of PGS1, the structural gene encoding PGP synthase, results in the complete loss of both PG and CL (Janitor et al, 1996;Chang et al, 1998a). The crd1⌬ mutant, which lacks CL synthase, has no detectable CL but accumulates PG (Jiang et al, 1997;Chang et al, 1998b;Tuller et al, 1998;Jiang et al, 2000;Pfeiffer et al, 2003;Zhong et al, 2004). The human taffazin gene (TAZ1), which is associated with Barth syndrome, encodes a transacylase that may be involved in the remodeling of CL (Xu et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Loss of Function ofKRE5Suppresses Temperature Sensitivity of Mutants Lacking Mitochondrial Anionic Lipids

Zhong

Gvozdenović-Jeremić

Webster

et al. 2005

MBoC

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Disruption of PGS1, which encodes the enzyme that catalyzes the committed step of cardiolipin (CL) synthesis, results in loss of the mitochondrial anionic phospholipids phosphatidylglycerol (PG) and CL. The pgs1⌬ mutant exhibits severe growth defects at 37°C. To understand the essential functions of mitochondrial anionic lipids at elevated temperatures, we isolated suppressors of pgs1⌬ that grew at 37°C. One of the suppressors has a loss of function mutation in KRE5, which is involved in cell wall biogenesis. The cell wall of pgs1⌬ contained markedly reduced ␤-1,3-glucan, which was restored in the suppressor. Stabilization of the cell wall with osmotic support alleviated the cell wall defects of pgs1⌬ and suppressed the temperature sensitivity of all CL-deficient mutants. Evidence is presented suggesting that the previously reported inability of pgs1⌬ to grow in the presence of ethidium bromide was due to defective cell wall integrity, not from "petite lethality." These findings demonstrated that mitochondrial anionic lipids are required for cellular functions that are essential in cell wall biogenesis, the maintenance of cell integrity, and survival at elevated temperature. INTRODUCTIONCardiolipin (CL), a unique anionic phospholipid with dimeric structure, is ubiquitous in eukaryotes and primarily found in the mitochondrial inner membrane . CL plays a key role in mitochondrial bioenergetics (Jiang et al., 2000; Greenberg, 2000, 2002;Schlame et al., 2000;Pfeiffer et al., 2003) and is also involved in mitochondrial biogenesis (Kawasaki et al., 1999;Jiang et al., 2000). Defective remodeling of CL is associated with Barth syndrome, a severe genetic disorder characterized by cardiomyopathy, neutropenia, skeletal myopathy, and respiratory chain defects (Vreken et al., 2000). The phenotype of Barth syndrome is dependent upon multiple factors that are not well understood (Barth et al., 1983(Barth et al., , 1996. Elucidation of the functions of CL will help to clarify the abnormalities associated with this disorder.The biosynthesis of CL is conserved in eukaryotic organisms. It occurs via three enzymatic reactions , including formation of phosphatidylglycerolphosphate (PGP) from CDP-DAG and glycerol-3-P, dephosphorylation of PGP to phosphatidylglycerol (PG), and condensation of CDP-DAG and PG to form CL. Disruption of PGS1, the structural gene encoding PGP synthase, results in the complete loss of both PG and CL (Janitor et al., 1996;Chang et al., 1998a). The crd1⌬ mutant, which lacks CL synthase, has no detectable CL but accumulates PG (Jiang et al., 1997;Chang et al., 1998b;Tuller et al., 1998;Jiang et al., 2000;Pfeiffer et al., 2003;Zhong et al., 2004). The human taffazin gene (TAZ1), which is associated with Barth syndrome, encodes a transacylase that may be involved in the remodeling of CL (Xu et al., 2003). Deletion of the yeast homolog of this gene, TAZ1, leads to decreased CL, aberrant CL acyl species, and accumulation of monolysocardiolipin . Mutants deficient in CL biosynthesis exhibit growth defects at elevat...

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Cardiolipin Stabilizes Respiratory Chain Supercomplexes

Cited by 728 publications

References 55 publications

The Cardiolipin Transacylase, Tafazzin, Associates with Two Distinct Respiratory Components Providing Insight into Barth Syndrome

The Cardiolipin Transacylase, Tafazzin, Associates with Two Distinct Respiratory Components Providing Insight into Barth Syndrome

Taz1, an Outer Mitochondrial Membrane Protein, Affects Stability and Assembly of Inner Membrane Protein Complexes: Implications for Barth Syndrome

Loss of Function ofKRE5Suppresses Temperature Sensitivity of Mutants Lacking Mitochondrial Anionic Lipids

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