Neurodegeneration: Liu et al.

DJ-1 is critical for the integrity and function of endoplasmic reticulum-mitochondria tethering

Yi Liu*, Sirui Jiang, Xiaopin Ma, Sandra L. Siedlak, Sandy Torres, Shengdi Chen, Xiongwei Zhu

 *Presenting author
Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA

DJ-1 is a protein with wide subcellular distribution and pleiotropic functions. The loss-of-function mutations of DJ-1 are associated with autosomal recessive early-onset Parkinson's disease yet the underlying pathogenic mechanism remains elusive. Prior studies suggest perturbation in endoplasmic reticulum (ER)-mitochondria tethering is involved in mitochondrial dysfunction and neurodegeneration in various neurodegenerative diseases including Alzheimer disease, Parkinson disease and Amyotrophic Lateral Sclerosis. Interestingly, we found that DJ-1 is an ER-mitochondria contacts resident protein in cultured cells and in the brain samples using both imaging and biochemical methods. In fact, by using co-immunoprecipitation and proximity ligation assay (PLA), we demonstrated that DJ-1 is part of the grp75-IP3R complexes and directly interacts with grp75. Moreover, in M17 neuroblastoma cells, loss of DJ-1 led to significant loss of ER-mitochondria tethering proteins in the mitochondria-associated membrane (MAM) and reduced grp75-IP3R interaction. PLA assay and ultrastructural study clearly demonstrated significantly reduced ER-mitochondria contacts in the DJ-1 knockout M17 cells. These disruptions were accompanied by disturbed mitochondrial calcium uptake following ER release and reduced ATP production in these cells. 

Our data suggest that DJ-1 is an endogenous component of the ER-mitochondria calcium transfer complex (i.e., IP3R-grp75-VDAC1 complex in the MAMs). DJ-1 deficiency triggers the disassembly of this complex and caused the disassociation of ER and mitochondria tethering. Our study unveiled a novel role of DJ-1 to facilitate the inter-organelle calcium signaling via stabilizing the IP3R-grp75-VDAC1 complex in the ER-mitochondria contact sites and suggest that impaired ER-mitochondria tethering could contribute to the pathogenic effects of DJ-1 mutations.