Altered ER-mitochondria contact impacts mitochondria calcium homeostasis and contributes to neurodegeneration in vivo in disease models.

Calcium (Ca) homeostasis is essential for neuronal function and survival. Altered Ca homeostasis has been consistently observed in neurological diseases. How Ca homeostasis is achieved in various cellular compartments of disease-relevant cell types is not well understood. Here we show in Parkinson's disease (PD) models that Ca transport from the endoplasmic reticulum (ER) to mitochondria through the ER-mitochondria contact site (ERMCS) critically regulates mitochondrial Ca (mito-Ca) homeostasis in dopaminergic (DA) neurons, and that the PD-associated PINK1 protein modulates this process. In mutant DA neurons, the ERMCS is strengthened and mito-Ca level is elevated, resulting in mitochondrial enlargement and neuronal death. Miro, a well-characterized component of the mitochondrial trafficking machinery, mediates the effects of PINK1 on mito-Ca and mitochondrial morphology, apparently in a transport-independent manner. Miro overexpression mimics loss-of-function effect, whereas inhibition of Miro or components of the ERMCS, or pharmacological modulation of ERMCS function, rescued mutant phenotypes. Mito-Ca homeostasis is also altered in the LRRK2-G2019S model of PD and the PAR-1/MARK model of neurodegeneration, and genetic or pharmacological restoration of mito-Ca level is beneficial in these models. Our results highlight the importance of mito-Ca homeostasis maintained by Miro and the ERMCS to mitochondrial physiology and neuronal integrity. Targeting this mito-Ca homeostasis pathway holds promise for a therapeutic strategy for neurodegenerative diseases.