Cardiolipin Molecular Species with Shorter Acyl Chains Accumulate in Saccharomyces cerevisiae Mutants Lacking the Acyl Coenzyme A-binding Protein Acb1p

Rijken, Pieter J.; Houtkooper, Riekelt H.; Akbari, Hana; Brouwers, Jos F.; Koorengevel, Martijn C.; Kruijff, Ben de; Frentzen, Margrit; Vaz, Frédéric M.; Kroon, Anton I.P.M. de

doi:10.1074/jbc.m109.016311

Cited by 21 publications

(15 citation statements)

References 59 publications

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“…This resembles results from a previous study, where loss of the acyl-CoA binding protein altered the supply of acylCoA metabolites and thus modified CL remodeling in yeasts (28). CoA is then trapped in long acyl-CoA molecules (stearoyl-and palmitoyl-CoA) that are not normally used in CL remodeling.…”

Section: Discussionsupporting

confidence: 71%

Acyl Coenzyme A Thioesterase Them5/Acot15 Is Involved in Cardiolipin Remodeling and Fatty Liver Development

Zhuravleva

Gut

Hynx

et al. 2012

Molecular and Cellular Biology

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f Acyl coenzyme A (acyl-CoA) thioesterases hydrolyze thioester bonds in acyl-CoA metabolites. The majority of mammalian thioesterases are ␣/␤-hydrolases and have been studied extensively. A second class of Hotdog-fold enzymes has been less well described. Here, we present a structural and functional analysis of a new mammalian mitochondrial thioesterase, Them5. Them5 and its paralog, Them4, adopt the classical Hotdog-fold structure and form homodimers in crystals. In vitro, Them5 shows strong thioesterase activity with long-chain acyl-CoAs. Loss of Them5 specifically alters the remodeling process of the mitochondrial phospholipid cardiolipin. Them5 ؊/؊ mice show deregulation of lipid metabolism and the development of fatty liver, exacerbated by a high-fat diet. Consequently, mitochondrial morphology is affected, and functions such as respiration and ␤-oxidation are impaired. The novel mitochondrial acyl-CoA thioesterase Them5 has a critical and specific role in the cardiolipin remodeling process, connecting it to the development of fatty liver and related conditions. T hioesterases participate in lipid metabolism by hydrolyzing thioester bonds in a variety of substrates, including fatty acidcoenzyme A (CoA) esters and palmitoylated proteins (17,19). Based on structural folds and the catalytic reaction mechanism, thioesterases are subdivided into ␣/␤-hydrolases and Hotdogfold thioesterases. The majority of mammalian thioesterases are the well-studied ␣/␤-hydrolases; the second class of Hotdog-fold enzymes has been described to a lesser extent (19). Of the eight Hotdog-fold proteins identified thus far in mammals, only a few participate in biological processes involving hydrolysis of acylCoAs (5). These are cytoplasmic Acot7 involved in eicosanoid metabolism, Acot11 and Acot12, which have a START domain, and cytoplasmic/mitochondrial Them2, which is induced by peroxisome proliferator-activated receptor ␣ (PPAR␣) and has been recently shown to regulate hepatic metabolism (5,8,16,18). The mammalian Hotdog thioesterases identified thus far have tetrameric or hexameric arrangements (26).Them5 is part of the mitochondrial proteome and is predicted to be a member of the Hotdog-fold family (5, 24). We show here that Them5, a novel thioesterase with strong specificity for long and unsaturated fatty acid-CoA esters, has the classical Hotdogfold with six ␤-sheets wrapped around a central ␣-helix. Them4 and Them5 form independent homodimers in crystals, suggesting that they represent a new group of mammalian hotdog thioesterases.Them5 Ϫ/Ϫ mice exhibit an increase in monolysocardiolipin, one of the specific metabolites of cardiolipin (CL). CL is a mitochondrion-specific phospholipid characterized by three to four linoleic acid chains (C 18:2 ) in its mature forms, particularly in mammals. Proper synthesis and remodeling (i.e., maintenance of the right acyl composition) of these highly unsaturated CL molecules is crucial for mitochondrial physiology, since CL interacts with many mitochondrial proteins. In the Barth syndrome, a...

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Section: Discussionsupporting

confidence: 71%

Acyl Coenzyme A Thioesterase Them5/Acot15 Is Involved in Cardiolipin Remodeling and Fatty Liver Development

Zhuravleva

Gut

Hynx

et al. 2012

Molecular and Cellular Biology

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“…S3 and S4 in the supplemental material). This is, again, different from what was observed for the S. cerevisiae acb1⌬ mutant, which showed growth defects with different carbon sources (35,37,50).…”

Section: Resultscontrasting

confidence: 45%

Secreted Acb1 Contributes to the Yeast-to-Hypha Transition in Cryptococcus neoformans

Zhao

Kirkman

et al. 2016

Appl Environ Microbiol

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Adaptation to stress by eukaryotic pathogens is often accompanied by a transition in cellular morphology. The human fungal pathogen Cryptococcus neoformans is known to switch between the yeast and the filamentous form in response to amoebic predation or during mating. As in the classic dimorphic fungal pathogens, the morphotype is associated with the ability of cryptococci to infect various hosts. Many cryptococcal factors and environmental stimuli, including pheromones (small peptides) and nutrient limitation, are known to induce the yeast-to-hypha transition. We recently discovered that secreted matricellular proteins could also act as intercellular signals to promote the yeast-to-hypha transition. Here we show that the secreted acyl coenzyme A (acyl-CoA)-binding protein Acb1 plays an important role in enhancing this morphotype transition. Acb1 does not possess a signal peptide. Its extracellular secretion and, consequently, its function in filamentation are dependent on an unconventional GRASP (Golgi reassembly stacking protein)-dependent secretion pathway. Surprisingly, intracellular recruitment of Acb1 to the secretory vesicles is independent of Grasp. In addition to Acb1, Grasp possibly controls the secretion of other cargos, because the grasp⌬ mutant, but not the acb1⌬ mutant, is defective in capsule production and macrophage phagocytosis. Nonetheless, Acb1 is likely the major or the sole effector of Grasp in terms of filamentation. Furthermore, we found that the key residue of Acb1 for acyl binding, Y80, is critical for the proper subcellular localization and secretion of Acb1 and for cryptococcal morphogenesis.A daptation to a changing environment by eukaryotic microbes is often accompanied by a transition in cellular morphology. The human fungal pathogen Cryptococcus neoformans causes devastating cryptococcal meningitis, which claims the lives of hundreds of thousands of people each year (1). Late diagnosis, limited options for antifungals, and the lack of vaccines to prevent cryptococcosis all contribute to the high mortality rate of this disease (2). C. neoformans typically grows as yeasts but can switch from yeasts to filaments (hyphae or pseudohyphae) in response to predation (e.g., by amoebae) or during sexual reproduction (3-7). As with many other fungal pathogens, the morphotype of C. neoformans shapes its interactions with various hosts (8). As we demonstrated recently, the hyphal form is associated with the attenuation of virulence in mouse models of cryptococcosis, because the hyphal morphotype elicits strong and protective host immune responses (9, 10). On the other hand, the hyphal morphotype assists the fungus in resisting predation from soil amoebae (8), increases its ability to explore the environment (11), and is linked to its unisexual and bisexual reproduction (3,(12)(13)(14). Thus, it is important to understand the factors that promote cryptococcal hyphal growth.Many environmental stimuli and a few cryptococcal factors that promote hyphal growth in C. neoformans have been identified ...

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“…Given that (14:0) 4 CL is found in select bacteria but not in mammalian mitochondria [60], the biological significance is limited for human physiology. There is precedence to show the accumulation of short chain fatty acids besides (14:0) 4 CL in yeast mutant models [61]. Perhaps, a significant increase in (14:0) 4 CL could occur in response to dietary intervention with short chain saturated fatty acids, such as those found in coconut oil.…”

Section: 0 Discussionmentioning

confidence: 99%

Distinct membrane properties are differentially influenced by cardiolipin content and acyl chain composition in biomimetic membranes

Pennington¹,

Fix²,

Sullivan³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Cardiolipin (CL) has a critical role in maintaining mitochondrial inner membrane structure. In several conditions such as heart failure and aging, there is loss of CL content and remodeling of CL acyl chains, which are hypothesized to impair mitochondrial inner membrane biophysical organization. Therefore, this study discriminated how CL content and acyl chain composition influenced select properties of simple and complex mitochondrial mimicking model membranes. We focused on monolayer excess area/molecule (a measure of lipid miscibility), bilayer phase transitions, and microdomain organization. In monolayer compression studies, loss of tetralinoleoyl [(18:2)4] CL content decreased the excess area/molecule. Replacement of (18:2)4CL acyl chains with tetraoleoyl [(18:1)4] CL or tetradocosahexaenoyl [(22:6)4] CL generally had little influence on monolayer excess area/molecule; in contrast, replacement of (18:2)4CL acyl chains with tetramyristoyl [(14:0)4] CL increased monolayer excess area/molecule. In bilayers, calorimetric studies showed that substitution of (18:2)4CL with (18:1)4CL or (22:6)4CL lowered the phase transition temperature of phosphatidylcholine vesicles whereas (14:0)4CL had no effect. Finally, quantitative imaging of giant unilamellar vesicles revealed differential effects of CL content and acyl chain composition on microdomain organization, visualized with the fluorescent probe Texas Red DHPE. Notably, microdomain areas were decreased by differing magnitudes upon lowering of (18:2)4CL content and substitution of (18:2)4CL with (14:0)4CL or (22:6)4CL. Conversely, exchanging (18:2)4CL with (18:1)4CL increased microdomain area. Altogether, these data demonstrate that CL content and fatty acyl composition differentially target membrane physical properties, which has implications for understanding how CL regulates mitochondrial activity and the design of CL-specific therapeutics.

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Cardiolipin Molecular Species with Shorter Acyl Chains Accumulate in Saccharomyces cerevisiae Mutants Lacking the Acyl Coenzyme A-binding Protein Acb1p

Cited by 21 publications

References 59 publications

Acyl Coenzyme A Thioesterase Them5/Acot15 Is Involved in Cardiolipin Remodeling and Fatty Liver Development

Acyl Coenzyme A Thioesterase Them5/Acot15 Is Involved in Cardiolipin Remodeling and Fatty Liver Development

Secreted Acb1 Contributes to the Yeast-to-Hypha Transition in Cryptococcus neoformans

Distinct membrane properties are differentially influenced by cardiolipin content and acyl chain composition in biomimetic membranes

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