Characterization of lymphoblast mitochondria from patients with Barth syndrome

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Bis(monoacylglycero)phosphate (BMP) is a unique lipid enriched in the late endosomes participating in the trafficking of lipids and proteins through this organelle. The de novo biosynthesis of BMP has not been clearly demonstrated. We investigated whether phosphatidylglycerol (PG) and cardiolipin (CL) could serve as precursors of de novo BMP synthesis using two different cellular models: CHO cells deficient in phosphatidylglycerophosphate (PGP) synthase, the enzyme responsible for the first step of PG synthesis; and human lymphoblasts from patients with Barth syndrome (BTHS), characterized by mutations in tafazzin, an enzyme implicated in the deacylation-reacylation cycle of CL. The biosynthesis of both PG and BMP was reduced significantly in the PGP synthase-deficient CHO mutants. Furthermore, overexpression of PGP synthase in the deficient mutants induced an increase of BMP biosynthesis. In contrast to CHO mutants, BMP biosynthesis and its fatty acid composition were not altered in BTHS lymphoblasts. Our results thus suggest that in mammalian cells, PG, but not CL, is a precursor of the de novo biosynthesis of BMP. Despite the decrease of de novo synthesis, the cellular content of BMP remained unchanged in CHO mutants, suggesting that other pathway(s) than de novo biosynthesis are also used for BMP synthesis.

Section: Bmp Biosynthesis and Fatty Acid Composition Are Not Altered supporting

confidence: 62%

“…Epstein-Barr virus-transformed lymphoblasts from control subjects and patients with BHTS (44) were cultured in suspension in RPMI 1640 medium in the presence of 10% (v/v) fetal bovine serum, 100 U/ml penicillin, and 100 mg/ml streptomycin at 37jC in a 5% CO 2 atmosphere as described previously (46).…”

Section: Cell Culturementioning

confidence: 99%

De novo biosynthesis of the late endosome lipid, bis(monoacylglycero)phosphate

Hullin-Matsuda

Kawasaki

Delton-Vandenbroucke

et al. 2007

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“…Although tetralinoleoyl-cardiolipin was the sole species in complex IV and the dominant species in the ADP-ATP carrier, an absolute requirement for symmetric cardiolipin cannot be postulated, because these proteins remain active in tafazzin mutants, in which symmetric cardiolipin virtually disappears (123,124).…”

Section: Assembly Of Mitochondrial Membranesmentioning

confidence: 99%

Thematic Review Series: Glycerolipids. Cardiolipin synthesis for the assembly of bacterial and mitochondrial membranes

Schlame

2008

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337

303

In this article, the formation of prokaryotic and eukaryotic cardiolipin is reviewed in light of its biological function. I begin with a detailed account of the structure of cardiolipin, its stereochemistry, and the resulting physical properties, and I present structural analogs of cardiolipin that occur in some organisms. Then I continue to discuss i) the de novo formation of cardiolipin, ii) its acyl remodeling, iii) the assembly of cardiolipin into biological membranes, and iv) the degradation of cardiolipin, which may be involved in apoptosis and mitochondrial fusion. Thus, this article covers the entire metabolic cycle of this unique phospholipid. It is shown that mitochondria produce cardiolipin species with a high degree of structural uniformity and molecular symmetry, among which there is often a dominant form with four identical acyl chains. The subsequent assembly of cardiolipin into functional membranes is largely unknown, but the analysis of crystal structures of membrane proteins has revealed a first glimpse into the underlying principles of cardiolipin-protein interactions. Disturbances of cardiolipin metabolism are crucial in the pathophysiology of human Barth syndrome and perhaps also play a role in diabetes and ischemic heart disease.-Schlame, M. Cardiolipin synthesis for the assembly of bacterial and mitochondrial membranes.

“…Up to now, CL and MLCL analyses in BTHS, with or without diagnostic intent, have been set up on lymphoblasts ( 18 ), lymphocytes ( 19 ), platelets (20)(21)(22), fi broblasts ( 23,24 ), neutrophils ( 25 ), leukocytes ( 26 ), bloodspots ( 27 ), and tissues ( 19 ). All these reports, including the validated methods ( 26,27 ), are based on lipid extraction followed by HPLC and ESI/MS analysis.…”

Section: Maldi-tof/msmentioning

confidence: 99%

Cardiolipin fingerprinting of leukocytes by MALDI-TOF/MS as a screening tool for Barth syndrome

Angelini

Lobasso

Gorgoglione

et al. 2015

mitochondrial respiratory chain dysfunction ( 1-4 ). It results from loss-of-function mutations of the tafazzin ( TAZ ) gene ( 5 ).The major consequence of this loss-of-function is the defi cient remodeling of the mitochondrial phospholipid cardiolipin (CL), a process that normally leads to the mature acyl composition ( 6, 7 ). CL is the signature lipid of mitochondria, where it is an important constituent of the inner membrane, essential for supercomplex formation, oxidative phosphorylation (i.e., mitochondrial energy metabolism), and protein import, and is capable of triggering mitophagy and mitochondria-mediated apoptosis (8)(9)(10)(11)(12)(13)(14)(15)(16). Because the remodeling of CL is deficient in BTHS, biochemical abnormalities in patients include a decreased level of mature CL (CLm), an increased level of monolysocardiolipin (MLCL), and altered CL acyl composition [i.e., the presence of immature CL (CLi) species].Historically, the diagnosis of BTHS has relied on identifi cation of the clinical symptoms accompanied by neutropenia and 3-MGCA and has then been confi rmed by the fi nding of TAZ mutations. More recently, assays of CL alone or of the ratio of CL to MLCL have been used in Europe. However, each of these diagnostic approaches has problems. There are multiple reports of false-negative disease detection by urinary organic acid screening ( 4 ). TAZ sequencing is relatively slow and expensive, and CL analysis involves many steps including extraction of lipids and isolation of CL molecular species by complex chromatographic techniques. Consequently, although measurement of CL/MLCL ratio has 100% diagnostic sensitivity and specifi city, it is only available in a few clinical laboratories