Cardiolipin Is Essential for Organization of Complexes III and IV into a Supercomplex in Intact Yeast Mitochondria

Zhang, Mei; Mileykovskaya, Eugenia; Dowhan, William

doi:10.1074/jbc.m504955200

Cited by 303 publications

(247 citation statements)

References 29 publications

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“…In higher eukaryotes, similar oligomerization has been observed (Schägger et al, 2004;Dudkina et al, 2005). The formation of supercomplexes is thought to increase the efficiency of respiration through both substrate channeling and sequestration of reactive intermediates and is thus of advantage for efficient respiration (Cruciat et al, 2000;Schägger and Pfeiffer, 2000;Zhang et al, 2005). 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.…”

Section: Introductionmentioning

confidence: 77%

“…This technique has been used to show that respiratory complexes associate in higher order complexes, or supercomplexes. Recent analysis demonstrates that supercomplex formation between complex III and IV plays an important role for respiratory chain function in intact organelles (Zhang et al, 2005). Similarly, yeast mutants of factors required for dimerization of the F 1 F o -ATPase show growth defects on nonfermentable carbon sources (Arnold et al, 1998).…”

Section: Taz1 and Respiratory Chain Complexesmentioning

confidence: 99%

“…The formation of supercomplexes is thought to increase the efficiency of respiration through both substrate channeling and sequestration of reactive intermediates and is thus of advantage for efficient respiration (Cruciat et al, 2000;Schägger and Pfeiffer, 2000;Zhang et al, 2005). 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).…”

Section: Introductionmentioning

confidence: 99%

“…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).…”

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confidence: 99%

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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

190

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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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Section: Introductionmentioning

confidence: 77%

Section: Taz1 and Respiratory Chain Complexesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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

190

150

View full text Add to dashboard Cite

show abstract

“…One paricular lipid in the mitochondrial IM is the diphosphatidylglycerol called cardiolipin (Zhang et al 2002). This lipid is synthesized within the mitochondrion and is important in the structural integrity of the IM and activities of the respiratory chain (Zhang et al 2005a). …”

mentioning

confidence: 99%