The Emerging and Diverse Roles of Bis(monoacylglycero) Phosphate Lipids in Cellular Physiology and Disease

Abstract

Although understudied relative to many phospholipids, accumulating evidence suggests that bis(monoacylglycero)phosphate (BMP) is an important class of regulatory lipid that plays key roles in lysosomal integrity and function. BMPs are rare in most mammalian tissues, comprising only a few percent of total cellular lipid content, but are elevated in cell types such as macrophages that rely heavily on lysosomal function. BMPs are markedly enriched in endosomal and lysosomal vesicles compared to other organelles and membranous structures, and their unique sn-1:sn-1' stereoconfiguration may confer stability within the hydrolytic lysosomal environment. BMP-enriched vesicles serve in endosomal-lysosomal trafficking and function as docking structures for the activation of lysosomal hydrolytic enzymes, notably those involved in the catabolic breakdown of sphingolipids. BMP levels are dysregulated in lysosomal storage disorders, phospholipidosis, metabolic diseases, liver and kidney diseases and neurodegenerative disorders. However, whether BMP alteration is a mediator or simply a marker of pathological states is unclear. Likewise, although BMP acyl chain composition may be altered with disease states, the functional significance of specific BMP species remains to be resolved. Newly developed tools for untargeted lipidomic analysis, together with a deeper understanding of enzymes mediating BMP synthesis and degradation, will help shed further light on the functional significance of BMPs in cellular physiology and pathology.

Keywords: bis(monoacylglycero)phosphate; lipidomics; lysobisphophatidic acid; lysosome.

Figure 1

Overview of bis(monoacylglycero)phosphate (BMP) publications and known BMP species. (a) Number of publications mentioning BMP in PubMed from 1999 to 2019. (b) Known BMP species variants, shown with fatty acyl side chains composed of oleic acid (FA C18:1) as an example.

Figure 2

Overview of the detection methods for BMPs. BMPs can be analyzed by antibody detection or by mass spectrometry. Mass spectrometry techniques use targeted or untargeted methods to measure BMPs. BMPs must be differentiated from isomeric phosphatidylglycerol (PG) species during mass spectrometry analysis, which can be accomplished by a number of methods including chromatography or derivatization.

Figure 3

Schematic of BMP’s functional role within lysosomes. BMP serves as a docking site and critical cofactor for acid sphingomyelinase (ASM), which metabolizes sphingomyelin (Sph) to ceramide (Cer) at intraluminal vesicles (inner vesicles). Cationic amphiphilic drugs (CADs) rapidly partition across cellular membranes and become protonated and sequestered within the acidic lysosomal lumen in a process termed ‘lysosomal trapping.’ Within the lysosome, CADs disrupt acid ASM-BMP interactions, thereby inhibiting ASM function and causing buildup of sphingomyelins. Altered sphingomyelin metabolism destabilizes the lysosomal membrane, which can lead to lysosomal membrane permeabilization (LMP), consequent lysosomal cathepsin protease release, and cell death.