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

Abstract

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.

Selective decrease of bis(monoacylglycero)phosphate content in macrophages by high supplementation with docosahexaenoic acid

“…we observed that increasing the synthesis of PG by phosphatidylglycerophosphate synthase overexpression was not associated with an enhanced formation of CL in CHO cells (29). Consistently, we did not measure any accumulation of CL after supplementation with 18:1/18:1-PG or 22:6/22:6-PG, confirming the absence of a tight correlation between PG and CL.…”

“…Numerous studies have clearly established that exogenous PG and cardiolipin (CL) could serve as precursors for BMP synthesis (25)(26)(27)(28). Recently, we have reported that PG, but not CL, is an endogenous precursor of BMP (29). Of interest, Waite et al (27) have pointed out some variability in the level of BMP synthesis with PG derived from different PL precursors, which they proposed to be related to differences in PG FA composition.…”

Lipid Sorting and Multivesicular Endosome Biogenesis

“…Indeed, it has been shown that two polyglycerophospholipids, phosphatidylglycerol (PG), a structural isomer of LBPA and cardiolipin, can be converted to LBPA in in vivo systems (Poorthuis and Hostetler 1975;Somerharju and Renkonen 1980;Amidon et al 1995). However, it was also shown that only PG, but not cardiolipin, serves as a possible precursor for de novo LBPA biosynthesis in vivo (Hullin-Matsuda et al 2007). Strikingly these studies also show that despite decreased de novo LBPA synthesis in cells deficient for PG synthesis, the total LBPA amount remains unchanged, indicating that some other biosynthetic pathway must exist.…”

Specific roles of phosphatidylglycerols in hosts and microbes

“…BMP is thought to be derived from PG since cells deficient in PG synthesis have reduced ability to produce this lipid (31). Remarkably, BMP was reported to date only in eukaryotes, with a strict endosome /lysosomes distribution, and it is still largely unknown how BMP is produced and transported to endo-lysosomes.…”