Bis(monoacylglycero)phosphate (BMP) is a signature lysosomal phospholipid that supports the catabolic functions of the lysosome. We recently demonstrated that BMP deficiency is associated with a variant of Batten disease, a neurodegenerative lysosomal storage disorder. This observation led us to investigate how BMP deficiency contributes to the previously reported accumulation of the ATP synthase c-ring in the lysosomes of Batten disease patients and preclinical models. The c-ring is an inner mitochondrial membrane (IMM) protein complex that interacts with cardiolipin, a mitochondrial phospholipid that shares structural features with BMP. Based on this, we hypothesised that BMP may perform an analogous function to cardiolipin in lysosomes. Specifically, we proposed that BMP preferentially interacts with the c-ring, dispersing it within lysosomal membranes and facilitating its degradation. To test this hypothesis, we conducted all-atom molecular dynamics simulations to examine the interactions of various BMP variants with the c-ring of human ATP synthase under different membrane conditions. We observed leaflet-specific preferential interactions of BMP with the protein interface. Replacement of BMP with anionic POPG lipids resulted in a lower binding affinity to the c-ring, indicating the importance of BMP's unique structure with respect to protein binding. Furthermore, BMP enrichment was enhanced when using the physiologically relevant di-22:6 BMP variant in membranes containing polyunsaturated lipids and cholesterol. Overall, our study suggests that BMP promotes lysosomal c-ring degradation via c-ring co-localisation, whereas BMP deficiency in Batten disease drives c-ring accumulation.
Starke, L. J., Hansen, E. K., Petkevicius, K., Duncan, A. L.
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