Mitochondrial Respiratory Chain Supercomplexes Are Destabilized in Barth Syndrome Patients

McKenzie, Matthew; Lazarou, Michael; Thorburn, David R.; Ryan, Michael

doi:10.1016/j.jmb.2006.06.057

Cited by 374 publications

(312 citation statements)

References 35 publications

(43 reference statements)

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“…Given the importance of CL in the proper functioning of many of the components of the oxidative phosphorylation machinery, a reasonable hypothesis for the defects in respiration in BTHS patients, and models alike, is that reduced CL content, altered acyl chain content, and/or the increased abundance of MLCL destabilize respiratory supercomplexes resulting in reduced respiratory efficiency. Consistent with this postulate, the assembly and stability of respiratory supercomplexes is compromised in fibroblasts derived from BTHS patients (McKenzie et al, 2006) and in one yeast BTHS model (Brandner et al, 2005). However, we recently demonstrated in another yeast BTHS model (a different strain than used in Brandner et al, 2005), that although there are moderate but significant changes in respiratory supercomplex function, there are no discernable defects in respiratory supercomplex assembly in the absence of Taz1p (Claypool et al, 2008).…”

Section: Introductionsupporting

confidence: 54%

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: Introductionsupporting

confidence: 54%

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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“…It has also been shown that Tafazzin defects result in destabilized OXPHOS supercomplexes , which in turn results in reduced steady-state levels of CI. These findings suggest that cardiolipin is essential for OXPHOS supercomplex stability, and that loss of supercomplex stability contributes to Barth syndrome pathogenesis [19].…”

Section: Oxphos Supercomplexesmentioning

confidence: 82%

“…In addition, the phospholipid cardiolipin is required for OX-PHOS supercomplex assembly and stability [19]. The majority of cardiolipin is found in the inner mitochondrial membrane where it is essential for mitochondrial function.…”

Section: Oxphos Supercomplexesmentioning

confidence: 99%

“…Cardiolipin has been shown to be vital for OXPHOS complex and supercomplex formation and stability [19][20][21]. As described previously, mutations in TAZ, which encodes the mitochondrial cardiolipin acyl-transferase, Tafazzin, result in reduced levels of mature tetralinoleoylcardiolipin in the inner mitochondrial membrane, with the subsequent destabilization of OXPHOS CI/CIII 2 /CIV 1-3 supercomplex and monomeric CI [19].…”

Section: Combined Lchad and Oxphos Defectsmentioning

confidence: 99%

“…Conversely, knockdown of LCHAD in Barth Syndrome patient lymphoblasts results in the accumulation of monolysocardiolipin [133]. Therefore, LCHAD may be essential for OXPHOS CI/CIII 2 /CIV 1-3 supercomplex and CI monomer stability and assembly via its ability to generate mature cardiolipin [19,133].…”

Section: Combined Lchad and Oxphos Defectsmentioning

confidence: 99%

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Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

Nsiah-Sefaa

McKenzie

2016

Bioscience Reports

Self Cite

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SynopsisMitochondria provide the main source of energy to eukaryotic cells, oxidizing fats and sugars to generate ATP . Mitochondrial fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two metabolic pathways which are central to this process. Defects in these pathways can result in diseases of the brain, skeletal muscle, heart and liver, affecting approximately 1 in 5000 live births. There are no effective therapies for these disorders, with quality of life severely reduced for most patients. The pathology underlying many aspects of these diseases is not well understood; for example, it is not clear why some patients with primary FAO deficiencies exhibit secondary OXPHOS defects. However, recent findings suggest that physical interactions exist between FAO and OXPHOS proteins, and that these interactions are critical for both FAO and OXPHOS function. Here, we review our current understanding of the interactions between FAO and OXPHOS proteins and how defects in these two metabolic pathways contribute to mitochondrial disease pathogenesis.Key words: disease, mitochondria, protein complex assembly, protein interactions, supercomplex. MITOCHONDRIAL METABOLISMMitochondria occupy almost all human cell types and are involved in essential metabolic and cellular processes, including calcium and iron homoeostasis, apoptosis, innate immunity and haeme biosynthesis [1]. However, the primary function of mitochondria is the production of energy in the form of ATP [2][3][4]. ATP is the body's energy currency, playing vital roles in cell differentiation, growth and reproduction, thermogenesis and powering the contraction of muscles for movement [1]. In humans, ATP is produced by two different processes; through the breakdown of glucose or other sugars in Abbreviations: ACAD9, acyl-CoA dehydrogenase 9; BN-PAGE, blue native polyacrylamide gel electrophoresis; CACT, carnitine acylcarnitine translocase; CI, oxidative phosphorylation complex I (NADH: ubiquinone oxidoreductase, EC 1.6.5.3); CII, oxidative phosphorylation complex II (succinate: ubiquinone oxidoreductase, EC 1.3.5.1); CIII, oxidative phosphorylation complex III (ubiquinol: ferricytochrome c oxidoreductase, EC 1.10.2.2); CIV, oxidative phosphorylation complex IV (cytochrome c oxidase, EC 1.9.3.1); COPP , complex one phylogenetic profile; CPT1, carnitine O-palmitoyltransferase 1; CPT2, carnitine O-palmitoyltransferase 2; CV, OXPHOS complex V (FoF 1 -ATP synthetase, EC; 3.6.3.14); ECHS1, enoyl-CoA hydratase, short chain 1, mitochondrial; ECI1, enoyl-CoA delta isomerase, 1; ETF, electron transfer flavoprotein; ETFA, electron transfer flavoprotein alpha subunit; ETFB, electron transfer flavoprotein beta subunit; ETF-QO, electron transfer flavoprotein: ubiquinone oxidoreductase; FAD, flavin adenine dinucleotide; FADH 2 , reduced flavin adenine dinucleotide; FAO, fatty acid β-oxidation; H 2 O, water; HADH, hydroxyacyl-CoA dehydrogenase; KAT, 3-ketoacyl-CoA thiolase, mitochondrial; LCAD, long chain acyl-CoA dehydrogenase; LCEH, long chain enoyl-CoA hydra...

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The role of nonbilayer phospholipids in mitochondrial structure and function

2017

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Edited by Wilhelm JustMitochondrial structure and function are influenced by the unique phospholipid composition of its membranes. While mitochondria contain all the major classes of phospholipids, recent studies have highlighted specific roles of the nonbilayer-forming phospholipids phosphatidylethanolamine (PE) and cardiolipin (CL) in the assembly and activity of mitochondrial respiratory chain (MRC) complexes. The nonbilayer phospholipids are cone-shaped molecules that introduce curvature stress in the bilayer membrane and have been shown to impact mitochondrial fusion and fission. In addition to their overlapping roles in these mitochondrial processes, each nonbilayer phospholipid also plays a unique role in mitochondrial function; for example, CL is specifically required for MRC supercomplex formation. Recent discoveries of mitochondrial PE-and CL-trafficking proteins and prior knowledge of their biosynthetic pathways have provided targets for precisely manipulating nonbilayer phospholipid levels in the mitochondrial membranes in vivo. Thus, the genetic mutants of these pathways could be valuable tools in illuminating molecular functions and biophysical properties of nonbilayer phospholipids in driving mitochondrial bioenergetics and dynamics.

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Mitochondrial Respiratory Chain Supercomplexes Are Destabilized in Barth Syndrome Patients

Cited by 374 publications

References 35 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

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

The role of nonbilayer phospholipids in mitochondrial structure and function

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