Tafazzin-dependent cardiolipin composition in C6 glioma cells correlates with changes in mitochondrial and cellular functions, and cellular proliferation

Gürtler, Sarah; Wolke, Carmen; Otto, Oliver; Heise, Nico; Scholz, Fritz; Laporte, Anna; Jörns, Anne; Weinert, Sönke; Döring, Mona; Jansing, Steffen; Gardemann, Andreas; Lendeckel, Uwe; Schild, Lorenz

doi:10.1016/j.bbalip.2019.01.006

Cited by 9 publications

(19 citation statements)

References 51 publications

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“…Data is shown as mean ± SD (n = 6) chains, which is in good agreement with earlier observations by us and others in BTHS patient derived fibroblasts. 19,20,[31][32][33][34][35] Following a recently published mathematical modeling approach, 16 we extracted the underlying fatty acid profile from mass spectrometric fragmentation data and found a significant increase of saturated fatty acids (16:0, palmitate and 18:0, stearate) and a depletion of 18:2 (presumably linoleic acid) in CLs of ΔTAZ cells compared to WT (Figure 1B).…”

Section: Tafazzin Knock-out Causes a Barth Syndrome-like Cardiolipin ...mentioning

confidence: 99%

The lipid environment modulates cardiolipin and phospholipid constitution in wild type and tafazzin‐deficient cells

Oemer

Koch

Wohlfarter

et al. 2021

J of Inher Metab Disea

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Deficiency of the transacylase tafazzin due to loss of function variants in the X‐chromosomal TAFAZZIN gene causes Barth syndrome (BTHS) with severe neonatal or infantile cardiomyopathy, neutropenia, myopathy, and short stature. The condition is characterized by drastic changes in the composition of cardiolipins, a mitochondria‐specific class of phospholipids. Studies examining the impact of tafazzin deficiency on the metabolism of other phospholipids have so far generated inhomogeneous and partly conflicting results. Recent studies showed that the cardiolipin composition in cells and different murine tissues is highly dependent on the surrounding lipid environment. In order to study the relevance of different lipid states and tafazzin function for cardiolipin and phospholipid homeostasis we conducted systematic modulation experiments in a CRISPR/Cas9 knock‐out model for BTHS. We found that—irrespective of tafazzin function—the composition of cardiolipins strongly depends on the nutritionally available lipid pool. Tafazzin deficiency causes a consistent shift towards cardiolipin species with more saturated and shorter acyl chains. Interestingly, the typical biochemical BTHS phenotype in phospholipid profiles of HEK 293T TAZ knock‐out cells strongly depends on the cellular lipid context. In response to altered nutritional lipid compositions, we measured more pronounced changes on phospholipids that were largely masked under standard cell culturing conditions, therewith giving a possible explanation for the conflicting results reported so far on BTHS lipid phenotypes.

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Section: Tafazzin Knock-out Causes a Barth Syndrome-like Cardiolipin ...mentioning

confidence: 99%

The lipid environment modulates cardiolipin and phospholipid constitution in wild type and tafazzin‐deficient cells

Oemer

Koch

Wohlfarter

et al. 2021

J of Inher Metab Disea

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“…56,57 Electrophysical properties, membrane curvature (cristae structure), and the assembling of membrane proteins depend on CL. 31,33,58 Thus, the observed VitB6-dependent alterations in CL could be responsible for the changes in membrane permeability and subsequently for the restriction in the capacity of oxidative phosphorylation in situations of VitB6 deficiency.…”

Section: Discussionmentioning

confidence: 99%

“…Thereby, the actual set of fatty acids present in CL has been found to be organism and tissue specific, 27 and is subject of change in response to physiological stimuli or under pathophysiological conditions. 28–30 It has been demonstrated that the fatty acid composition of CL can affect mitochondrial structure and biogenesis, 28,30,31 the activity and organization of mitochondrial membrane proteins and respiratory chain complexes, 32–34 and the efficiency of oxidative phosphorylation. 35–38…”

Section: Introductionmentioning

confidence: 99%

Vitamin B6 deficiency in new born rats affects hepatic cardiolipin composition and oxidative phosphorylation

Wolke

Gürtler

Peter

et al. 2019

Exp Biol Med (Maywood)

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Vitamin B6 deficiency during pregnancy translates into a severe vitamin B6 deficiency (plasma levels decreased by 97%) in new-born rats. Further, hallmarks are increased (+89%) concentrations of homocysteine, gross changes in gene methylation and expression, and metabolic alterations including lipid metabolism. This study focuses on determining the effects of vitamin B6-deficiency on cardiolipin composition and oxidative phosphorylation in liver. For this purpose, hepatic cardiolipin composition was analyzed by means of LC/MS/MS, and mitochondrial oxygen consumption was determined by using a Clark-type electrode in a rat model of vitamin B6 deficiency. Liver mitochondria from new-born rats with pre-term vitamin B6 deficiency responded with substantial alterations in cardiolipin composition that include the following changes in the amounts of cardiolipin incorporated fatty acids: increase in C16, decrease in C18, decrease in saturated fatty acid, as well as increase in amount of oxidized cardiolipin species. These changes were accompanied by significantly decreased capacity of oxidative phosphorylation. In conclusion, vitamin B6 deficiency in new born rats induces massive alterations of cardiolipin composition and function of liver mitochondria. These findings support the importance of sufficient periconceptional supply of vitamin B6 to prevent vitamin B6 deficiency. Impact statement Vitamin B6 (VitB6) is an active co-enzyme for more than 150 enzymes and is required for a great diversity of biosynthesis and metabolic reactions. There is an increased need for VitB6 during pregnancy and sufficient supply of VitB6 is crucial for the prevention of cleft palate and neural tube defects. We show that liver mitochondria from new-born rats with pre-term VitB6 deficiency respond with substantial alterations in cardiolipin (CL) composition and in the amount of oxidized CL species. These changes are associated with a decrease in the efficiency of oxidative phosphorylation. The results of this study support the significance of sufficient supply of VitB6 during pregnancy (and periconceptional) for diminishing the number of early abortions and minimizing malformation. The established link between VitB6 deficiency, CL composition, and mitochondrial respiration/energy production provides mechanistic insight as to how the VitB6 deficiency translates into the known pathophysiological and clinically relevant conditions.

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“…In addition, in C6 glioma cells, tafazzin knock-down in the presence of linoleic acid reduced the capacity of oxidative phosphorylation [57], mitochondrial complex I function, and increased glycolytic activity [58]. All those changes were accompanied by a dramatic reduction in cell proliferation [57,58]. It has already been demonstrated that the decrease in CL content affects the assembly of the ETC supercomplex [10].…”

Section: Role Of CL In Metabolic Reprogrammingmentioning

confidence: 97%

“…In all mentioned mouse brain tumor types, the activity of mitochondrial respiratory chain complexes I and II, as well as overall activity of mitochondrial ETC, was decreased [56]. In addition, in C6 glioma cells, tafazzin knock-down in the presence of linoleic acid reduced the capacity of oxidative phosphorylation [57], mitochondrial complex I function, and increased glycolytic activity [58]. All those changes were accompanied by a dramatic reduction in cell proliferation [57,58].…”

Section: Role Of CL In Metabolic Reprogrammingmentioning

confidence: 99%

Cardiolipin, the Mitochondrial Signature Lipid: Implication in Cancer

Ahmadpour

Mahéo

Servais

et al. 2020

IJMS

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Cardiolipins (CLs) are specific phospholipids of the mitochondria composing about 20% of the inner mitochondria membrane (IMM) phospholipid mass. Dysregulation of CL metabolism has been observed in several types of cancer. In most cases, the evidence for a role for CL in cancer is merely correlative, suggestive, ambiguous, and cancer-type dependent. In addition, CLs could play a pivotal role in several mitochondrial functions/parameters such as bioenergetics, dynamics, mitophagy, and apoptosis, which are involved in key steps of cancer aggressiveness (i.e., migration/invasion and resistance to treatment). Therefore, this review focuses on studies suggesting that changes in CL content and/or composition, as well as CL metabolism enzyme levels, may be linked with the progression and the aggressiveness of some types of cancer. Finally, we also introduce the main mitochondrial function in which CL could play a pivotal role with a special focus on its implication in cancer development and therapy.

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Tafazzin-dependent cardiolipin composition in C6 glioma cells correlates with changes in mitochondrial and cellular functions, and cellular proliferation

Cited by 9 publications

References 51 publications

The lipid environment modulates cardiolipin and phospholipid constitution in wild type and tafazzin‐deficient cells

The lipid environment modulates cardiolipin and phospholipid constitution in wild type and tafazzin‐deficient cells

Vitamin B6 deficiency in new born rats affects hepatic cardiolipin composition and oxidative phosphorylation

Cardiolipin, the Mitochondrial Signature Lipid: Implication in Cancer

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