Barth syndrome mutations that cause tafazzin complex lability

Claypool, Steven M.; Whited, Kevin; Srijumnong, Santi; Han, Xianlin; Koehler, Carla M.

doi:10.1083/jcb.201008177

Cited by 60 publications

(86 citation statements)

References 60 publications

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“…In organello import into mitochondria was performed exactly as described previously (38) using mitochondria isolated from D273-10B yeast grown in rich lactate. The mitochondrial proton-motive force was collapsed where indicated by pre-incubating mitochondria for 5 min at 30°C with 1 M valinomycin and 5 M carbonyl cyanide m-chlorophenyl hydrazine.…”

Section: Methodsmentioning

confidence: 99%

Phosphatidylserine Decarboxylase 1 Autocatalysis and Function Does Not Require a Mitochondrial-specific Factor

Onguka¹,

Calzada²,

Ogunbona³

et al. 2015

Journal of Biological Chemistry

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Background: Autocatalytic processing is required for Psd1p function. Molecular requirements for Psd1p autocatalysis are largely undefined. Results: Psd1p autocatalysis occurs in yeast mutants lacking its substrate or mitochondrial-specific lipids. Furthermore, Psd1p re-directed to the endoplasmic reticulum undergoes autocatalysis and is functional in vivo. Conclusion: Psd1p autocatalysis does not require its substrate or mitochondrial-specific lipids, proteins, or co-factors. Significance: Once membrane-embedded, Psd1p is autocatalytically self-sufficient.

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Section: Methodsmentioning

confidence: 99%

Phosphatidylserine Decarboxylase 1 Autocatalysis and Function Does Not Require a Mitochondrial-specific Factor

Onguka¹,

Calzada²,

Ogunbona³

et al. 2015

Journal of Biological Chemistry

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“…In eukaryotic cells, cardiolipin is synthesized by two pathways (de novo synthesis and remodeling of the pre-existing protein) that involve enzymatic activities that, under certain scenarios, are indispensable for cell viability. For example, mitochondrial dysfunction ensues in Barth syndrome -where tafazzin is mutated (Claypool et al, 2008(Claypool et al, , 2006(Claypool et al, , 2011 -and when Cls1 is defective (Pineau et al, 2013). In our related studies, bacterial infection with Staphylococcus aureas downregulates Cls1 levels through activation of another E3 ubiquitin ligase, SCF-Fbxo15, which decreases cardiolipin availability and disrupts mitochondrial function in lung epithelial cells (Chen et al, 2014a).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, potentially, many processes that result in impaired remodeling of cardiolipin through dysregulation of mitochondrial acyltransferases could result in decreased cardiolipin generation, mitochondrial structural anomalies and impairment in cellular bioenergetics. One such example is Barth syndrome, in which a mutation causes decreased tafazzin function, leading to a multitude of clinical effects, coupled with impaired cellular bioenergetics due to reduced biologically active cardiolipin (Claypool et al, 2008(Claypool et al, , 2006(Claypool et al, , 2011Whited et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

LPS impairs oxygen utilization in epithelia by triggering degradation of the mitochondrial enzyme Alcat1

Zou

Synan

et al. 2016

Journal of Cell Science

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Cardiolipin (also known as PDL6) is an indispensable lipid required for mitochondrial respiration that is generated through de novo synthesis and remodeling. Here, the cardiolipin remodeling enzyme, acyl-CoA:lysocardiolipin-acyltransferase-1 (Alcat1; SwissProt ID, Q6UWP7) is destabilized in epithelia by lipopolysaccharide (LPS) impairing mitochondrial function. Exposure to LPS selectively decreased levels of carbon 20 (C 20 )-containing cardiolipin molecular species, whereas the content of C 18 or C 16 species was not significantly altered, consistent with decreased levels of Alcat1. Alcat1 is a labile protein that is lysosomally degraded by the ubiquitin E3 ligase Skp-Cullin-F-box containing the Fbxo28 subunit (SCFFbxo28) that targets Alcat1 for monoubiquitylation at residue K183. Interestingly, K183 is also an acetylation-acceptor site, and acetylation conferred stability to the enzyme. Histone deacetylase 2 (HDAC2) interacted with Alcat1, and expression of a plasmid encoding HDAC2 or treatment of cells with LPS deacetylated and destabilized Alcat1, whereas treatment of cells with a pan-HDAC inhibitor increased Alcat1 levels. Alcat1 degradation was partially abrogated in LPS-treated cells that had been silenced for HDAC2 or treated with MLN4924, an inhibitor of Cullin-RING E3 ubiquitin ligases. Thus, LPS increases HDAC2-mediated Alcat1 deacetylation and facilitates SCF-Fbxo28-mediated disposal of Alcat1, thus impairing mitochondrial integrity.

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“…Localization studies showed that wild-type Taz1p localizes to the inner and outer mitochondrial membranes, facing the intermembrane space (6,14,15). When yeast was used as a system to model Taz1p mutations associated with BTHS, a subset of Taz1p mutants correctly localized to the intermembrane space but assembled in complexes that were not functional (6) or were degraded by the intermembrane space i-AAA protease Yme1 (12). Another subset of mutants localized to the mitochondrial matrix, suggesting that mistargeting of tafazzin resulted in BTHS in a subset of patients (6).…”

mentioning

confidence: 99%

“…Tafazzin functions as a transacylase in the CL maturation pathway by replacing saturated chains with unsaturated chains (7). A hallmark of BTHS is the accumulation of the CL remodeling intermediate monolyso-CL, which lacks a fatty acid (6,12).…”

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confidence: 99%

The Taz1p Transacylase Is Imported and Sorted into the Outer Mitochondrial Membrane via a Membrane Anchor Domain

2013

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dMutations in the mitochondrial transacylase tafazzin, Taz1p, in Saccharomyces cerevisiae cause Barth syndrome, a disease of defective cardiolipin remodeling. Taz1p is an interfacial membrane protein that localizes to both the outer and inner membranes, lining the intermembrane space. Pathogenic point mutations in Taz1p that alter import and membrane insertion result in accumulation of monolysocardiolipin. In this study, we used yeast as a model to investigate the biogenesis of Taz1p. We show that to achieve this unique topology in mitochondria, Taz1p follows a novel import pathway in which it crosses the outer membrane via the translocase of the outer membrane and then uses the Tim9p-Tim10p complex of the intermembrane space to insert into the mitochondrial outer membrane. Taz1p is then transported to membranes of an intermediate density to reach a location in the inner membrane. Moreover, a pathogenic mutation within the membrane anchor (V224R) alters Taz1p import so that it bypasses the Tim9p-Tim10p complex and interacts with the translocase of the inner membrane, TIM23, to reach the matrix. Critical targeting information for Taz1p resides in the membrane anchor and flanking sequences, which are often mutated in Barth syndrome patients. These studies suggest that altering the mitochondrial import pathway of Taz1p may be important in understanding the molecular basis of Barth syndrome.

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Barth syndrome mutations that cause tafazzin complex lability

Abstract: Complexes containing tafazzin, which remodels newly synthesized cardiolipin, are destabilized by mutations associated with Barth syndrome.

Cited by 60 publications

References 60 publications

Phosphatidylserine Decarboxylase 1 Autocatalysis and Function Does Not Require a Mitochondrial-specific Factor

Phosphatidylserine Decarboxylase 1 Autocatalysis and Function Does Not Require a Mitochondrial-specific Factor

LPS impairs oxygen utilization in epithelia by triggering degradation of the mitochondrial enzyme Alcat1

The Taz1p Transacylase Is Imported and Sorted into the Outer Mitochondrial Membrane via a Membrane Anchor Domain

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