Loss of Cardiolipin Leads to Perturbation of Acetyl-CoA Synthesis

Raja, Vaishnavi; Joshi, Amit; Li, Guiling; Maddipati, Krishna Rao; Greenberg, Miriam L.

doi:10.1074/jbc.m116.753624

Cited by 34 publications

(30 citation statements)

References 83 publications

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“…A reduced sugar diet does not exacerbate the exercise intolerance of TAZ À/À mutants Due to evidence that low-sugar media is detrimental to CL knockout yeast (Raja et al 2017), we also measured the runspan of TAZ +/+ and TAZ À/À flies fed a 5% glucose diet. Reduced glucose availability had no detrimental effect on mutant endurance (Fig.…”

Section: Resultsmentioning

confidence: 99%

Drosophila tafazzinmutants have impaired exercise capacity

2018

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Cardiolipin (CL) is a mitochondrial phospholipid that helps maintain normal structure of the inner mitochondrial membrane and stabilize the protein complexes of the electron transport chain to promote efficient ATP synthesis. Tafazzin, an acyl‐transferase, is required for synthesis of the mature form of CL. Mutations in the tafazzin (TAZ) gene are associated with a human disorder known as Barth syndrome. Symptoms of Barth syndrome often include muscle weakness and exercise intolerance. Previous work demonstrates that Drosophila Taz mutants exhibit motor weakness, as measured by reduced flying and climbing abilities. However, Drosophila TAZ mutants’ baseline endurance or response to endurance exercise training has not been assessed. Here, we find that TAZ mutants have reduced endurance and do not improve following a stereotypical exercise training paradigm, indicating that loss of TAZ function leads to exercise intolerance in Drosophila. Although cardiac phenotypes are observed in human Barth syndrome patients, TAZ mutants had normal resistance to cardiac pacing. In the future, endurance may be a useful screening tool to identify additional genetic modifiers of tafazzin.

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Section: Resultsmentioning

confidence: 99%

Drosophila tafazzinmutants have impaired exercise capacity

2018

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“…Although the specific mechanisms leading to the metabolic changes in BTHS are unknown, they suggest that CL, long known to be required for oxidative phosphorylation and bioenergetics (2,3), is also required for optimal intermediary metabolism. This functional role is supported by studies in yeast strongly suggesting that CL deficiency leads to defects in the TCA cycle (32,33). Raja et al (32) showed that yeast cells that cannot synthesize CL (crd1⌬) exhibit decreased levels of acetyl-CoA.…”

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confidence: 85%

Cardiolipin-induced activation of pyruvate dehydrogenase links mitochondrial lipid biosynthesis to TCA cycle function

Lou

Raja

et al. 2019

Journal of Biological Chemistry

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Edited by George M. Carman Cardiolipin (CL) is the signature phospholipid of mitochondrial membranes. Although it has long been known that CL plays an important role in mitochondrial bioenergetics, recent evidence in the yeast model indicates that CL is also essential for intermediary metabolism. To gain insight into the function of CL in energy metabolism in mammalian cells, here we analyzed the metabolic flux of [U-13 C]glucose in a mouse C2C12 myoblast cell line, TAZ-KO, which is CL-deficient because of CRISPR/Cas9-mediated knockout of the CL-remodeling enzyme tafazzin (TAZ). TAZ-KO cells exhibited decreased flux of [U-13 C]glucose to [ 13 C]acetyl-CoA and M2 and M4 isotopomers of tricarboxylic acid (TCA) cycle intermediates. The activity of pyruvate carboxylase, the predominant enzyme for anaplerotic replenishing of the TCA cycle, was elevated in TAZ-KO cells, which also exhibited increased sensitivity to the pyruvate carboxylase inhibitor phenylacetate. We attributed a decreased carbon flux from glucose to acetyl-CoA in the TAZ-KO cells to a ϳ50% decrease in pyruvate dehydrogenase (PDH) activity, which was observed in both TAZ-KO cells and cardiac tissue from TAZ-KO mice. Protein-lipid overlay experiments revealed that PDH binds to CL, and supplementing digitonin-solubilized TAZ-KO mitochondria with CL restored PDH activity to WT levels. Mitochondria from TAZ-KO cells exhibited an increase in phosphorylated PDH, levels of which were reduced in the presence of supplemented CL. These findings indicate that CL is required for optimal PDH activation, generation of acetyl-CoA, and TCA cycle function, findings that link the key mitochondrial lipid CL to TCA cycle function and energy metabolism. The phospholipid cardiolipin (CL) 8 is the signature lipid of mitochondrial membranes. It interacts with a wide variety of mitochondrial proteins (1) and has multiple roles in mitochondrial biogenesis as well as other cellular functions (2-4). Loss of CL leads to deficiencies in respiratory function, mitochondrial membrane potential, and ATP synthesis (1, 5-7). CL that is synthesized de novo has predominantly saturated fatty acids (8). However, the lipid is then remodeled via phospholipase-mediated deacylation to form monolysocardiolipin (MLCL), which is subsequently acylated by the enzyme tafazzin to synthesize CL with predominantly unsaturated fatty acids (9, 10). Abnormal CL composition is associated with several human disorders, including diabetes, Alzheimer's disease, and Parkinson's disease (11-13). However, Barth syndrome (BTHS) is the only disorder identified to date that is caused by altered CL metabolism (14, 15). BTHS is a severe X-linked disorder characterized by dilated cardiomyopathy, skeletal myopathy, neutropenia, exercise intolerance, lactic acidosis, and sudden death from arrhythmia (16-18). The underlying cause of BTHS is mutations in the tafazzin (TAZ) gene, which codes for the transacylase that remodels CL (10, 19). As a result, BTHS patients exhibit an aberrant CL profile characterized by decreased tot...

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“…The absence of CL destabilizes AAC complex and its interaction with MRC supercomplexes, reducing the efficiency of mitochondrial ATP synthesis and its transport outside of mitochondria . A recent study has uncovered a role of CL in acetyl CoA biosynthesis via possible interaction with OMM localized acetyl CoA synthetase . Interestingly, CL deficiency also leads to defects in mitochondrial protein import pathways.…”

Section: Role Of CL In Mitochondrial Structure and Functionmentioning

confidence: 99%

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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Loss of Cardiolipin Leads to Perturbation of Acetyl-CoA Synthesis

Cited by 34 publications

References 83 publications

Drosophila tafazzinmutants have impaired exercise capacity

Drosophila tafazzinmutants have impaired exercise capacity

Cardiolipin-induced activation of pyruvate dehydrogenase links mitochondrial lipid biosynthesis to TCA cycle function

The role of nonbilayer phospholipids in mitochondrial structure and function

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