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Discovery of phosphatidylserine-deficient small extracellular vesicle subpopulation with super long blood circulation

ABSTRACT: Small extracellular vesicles (sEVs) are important mediators of intercellular communication with respect to diverse pathophysiological processes. The heterogeneity of sEV populations is a key factor in pursuing the sEV-related translational and basic research into forward but remains challenging for unraveling. Here, we discovered novel phosphatidylserine (PS; marker for sEV uptake by macrophage)-deficient sEV subpopulations which possessed super long blood circulation through escape from the uptake by macrophages (main player of the rapid sEV clearance from blood). PS(-)-sEVs were identified in various cultured-cells as a minor population. Meanwhile, circulating somatic cell-derived sEVs in the blood were found to be majorly PS(-)-sEVs, which were caused by rapid uptake of PS(+)-sEVs by macrophages within 10 min after entry into the circulation. These results suggest endogenous PS(-)-sEVs could truly be the key player of sEV-mediated intracellular communication and that PS(-)-sEVs can be a good target for sEV-based diagnosis as well as a potent candidate for sEV-based delivery carrier. Our findings shift the paradigm for further understanding the biology as well as for the translational applications of sEV.

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Yoshinobu Takakura

PROVIDER: PXD019244 | JPOST Repository | Thu Jul 08 00:00:00 BST 2021

REPOSITORIES: jPOST

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			Action	DRS
	190616ko02NT_gLuc_LA_1.maxq.dat	Other
	190616ko02NT_gLuc_LA_1.maxq.txt	Txt
	190616ko02NT_gLuc_LA_1.raw	Raw
	190616ko03MD_gLuc_Lamp2C_1.maxq.dat	Other
	190616ko03MD_gLuc_Lamp2C_1.maxq.txt	Txt

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Project description:Chronic low-grade inflammation is a hallmark of aging, but its etiology is not well understood. Mitochondrial dysfunction has been linked to both cellular senescence and age-related inflammation or inflammaging but fundamental mechanisms underlying these links are unclear. We analyzed age-related gene expression in different human tissues and discovered that in blood, the mRNA expression of Mitochondrial Calcium Uniporter (MCU) and its regulatory subunit MICU1 correlated inversely with age. MCU is the pore-forming subunit of a Ca2+-selective ion channel complex residing in the mitochondrial inner membrane and is the main conduit for Ca2+-influx into the mitochondrial matrix. Based on these findings we tested the simple hypothesis that mitochondrial Ca2+ uptake capacity of macrophages decreases with age. We found a significant reduction in the mitochondrial Ca2+-uptake capacity of macrophages derived from aged (80-90 weeks) mice. Notably, these macrophages display amplified cytosolic Ca2+ elevations and increased inflammatory output. To test the salience of mitochondrial calcium uptake in regulating macrophage inflammatory output, we deleted Mcu selectively in macrophages. The Mcu-/- macrophages of young mice (<25 weeks) express more inflammatory genes at baseline and show a hyper-inflammatory response when stimulated. We show that reduced mitochondrial Ca2+ amplifies cytosolic Ca2+ oscillations and potentiates downstream NFkB activation, which is central to inflammation. The regulation of inflammatory response by mitochondrial Ca2+ uptake is also seen readily in human macrophages. The siRNA-mediated knockdown of MCU in human blood derived macrophages recapitulates the phenomenon – the mitochondrial Ca2+-uptake is greatly reduced, cytosolic Ca2+ elevations are more pronounced, and the macrophages are hyper-inflammatory. Our findings pinpoint the MCU complex as a keystone molecular apparatus that links age-related changes in mitochondrial physiology to macrophage-mediated inflammation. Resident macrophages are intrinsic to every organ system and the steady erosion of their mitochondrial Ca2+-uptake capacity may play a germinal or exacerbating role in many age-related neurodegenerative, cardiometabolic, renal and musculoskeletal diseases that afflict us.

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Discovery of phosphatidylserine-deficient small extracellular vesicle subpopulation with super long blood circulation

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