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

Abstract

Calcium (Ca²⁺) homeostasis is essential for neuronal function and survival. Altered Ca²⁺ homeostasis has been consistently observed in neurological diseases. How Ca²⁺ homeostasis is achieved in various cellular compartments of disease-relevant cell types is not well understood. Here we show in <i>Drosophila</i> Parkinson's disease (PD) models that Ca²⁺ transport from the endoplasmic reticulum (ER) to mitochondria through the ER-mitochondria contact site (ERMCS) critically regulates mitochondrial Ca²⁺ (mito-Ca²⁺) homeostasis in dopaminergic (DA) neurons, and that the PD-associated PINK1 protein modulates this process. In <i>PINK1</i> mutant DA neurons, the ERMCS is strengthened and mito-Ca²⁺ 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-Ca²⁺ and mitochondrial morphology, apparently in a transport-independent manner. Miro overexpression mimics <i>PINK1</i> loss-of-function effect, whereas inhibition of Miro or components of the ERMCS, or pharmacological modulation of ERMCS function, rescued <i>PINK1</i> mutant phenotypes. Mito-Ca²⁺ 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-Ca²⁺ level is beneficial in these models. Our results highlight the importance of mito-Ca²⁺ homeostasis maintained by Miro and the ERMCS to mitochondrial physiology and neuronal integrity. Targeting this mito-Ca²⁺ homeostasis pathway holds promise for a therapeutic strategy for neurodegenerative diseases.