| Loss-of-function mutations of DJ-1 gene cause familial early-onset Parkinson’s disease.Besides,DJ-1 protein deficiency was found in sporadic PD.Intracellular DJ-1 is mainly distributed in cytoplasm,nucleus and mitochondria.DJ-1 owns different roles according to its different cell sites.DJ-1 in cytoplasm acts as an antioxidant response sensor to exert anti-oxidative stress.DJ-1 in the nucleus acts as a transcriptional factor to regulate the expression of some genes.Part of DJ-1 is distributed in mitochondria and regulates mitochondrial function.Through the direct and tight junction,a fraction of endoplasmic reticulum(ER)membrane and the mitochondrial outer membrane form a specialized,synaptic-like structure,the endoplasmic reticulummitochondrial contacts,a.k.a.Mitochondria-Associated ER Membrane,MAM.MAM has a series of functions such as regulation of intracellular calcium signaling,lipid synthesis,autophagosome formation,and mitochondrial division/fusion.In mammalian cells,the molecular basis for the formation of the MAM structure between the endoplasmic reticulum and the mitochondria is the 4 pairs of transmembrane membrane protein complexes(i.e.the MAM tethering complexes): IP3Rgrp75-VDAC1 complex,VAPB-PTPIP51 complex,Bap31-Fis1 complex and MFN2-MFN1/2 hetero/homo-dimer.Structural and functional abnormalities of MAM are widely involved in neurodegenerative diseases including Alzheimer’s disease(AD),PD,and ALS.In PD,PD-related proteins a-Synuclein and Parkin have been identified to be distributed in MAM.Intracellular accumulation of a-Syn or mutant a-Syn binds to the VAPB-PTPIP51 complex and disrupts the stability of the complex,resulting in MAM destruction and ER-mitochondrial calcium transfer blockage.Recently,an evidence suggests that DJ-1 is distributed in mouse brain MAM,but its functions and action mechanisms in MAM remains largely unknown.As DJ-1 plays an important role in both f PD and s PD,and MAM involves a series of key cellular functions.Therefore,we wondered that how DJ-1 acts in MAM,then we performed a series of studies to explore the function and mechanism of action of DJ-1 in MAM.We first demonstrated that DJ-1 is a MAM protein in human neuroblastoma M17 cells and human brain tissue samples.Lacking of DJ-1 caused difficulty for MAM formation.Futhermore,electron microscopic study revealed a disrupted ER mitochondria tethering in DJ-1 deficient cells.And subcellular calcium monitoring showed that DJ-1deficiency caused disordered intra-MAM calcium signaling,including endoplasmic reticulum calcium release impairment,endoplasmic reticulum calcium overloading,and mitochondrial calcium uptake impairment.What’s more,we discovered the molecular mechanism by which DJ-1 deficiency leads to MAM structural and functional abnormalities.IP3R-grp75-VDAC1 is a calcium transport channel located at MAM from which calcium flow out from the endoplasmic reticulum and into the mitochondria.DJ-1 in the MAM is a component of the endoplasmic reticulum-mitochondrial calcium transport complex by interacting with the IP3R-grp75-VDAC1 complex.Defects in DJ-1tirggered the disasemmbly of the IP3R-grp75-VDAC1 complex.In addition,DJ-1 may maintain the normal conformation of IP3 R through direct interaction with IP3 R,because our study found that DJ-1deficiency leads to the inability of IP3 R to degrade normally and aggregates in MAM.It is obvious that these accumulated aggregated IP3 Rs were futile status.In summary,we found that DJ-1 in MAM is involved in maintaining the structural and functional integrities of the ER-mitochondria contacts;DJ-1 is a endogenous component of the ER-mitochondrial calcium transfer complex,thereby ensuring normal calcium signaling between these two organelles.This novel role and mechanism of DJ-1 in MAM is of great significance in adding the knowledgement of pathogenesis of Parkinson’s disease and may cast some light on the therapeutic targets or strategies of this disease. |
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