Polo Kinase Phosphorylates Miro to Control ER-Mitochondria Contact Sites and Mitochondrial Ca(2+) Homeostasis in Neural Stem Cell Development.

Summary Mitochondria play central roles in buffering intracellular Ca 2+ transients. While basal mitochondrial Ca 2+ (Ca 2+ mito ) is needed to maintain organellar physiology, Ca 2+ mito overload can lead to cell death. How Ca 2+ mito homeostasis is regulated is not well understood. Here we show that Miro, a known component of the mitochondrial transport machinery, regulates Drosophila neural stem cell (NSC) development through Ca 2+ mito homeostasis control, independent of its role in mitochondrial transport. Miro interacts with Ca 2+ transporters at the ER-mitochondria contact site (ERMCS). Its inactivation causes Ca 2+ mito depletion and metabolic impairment, whereas its overexpression results in Ca 2+ mito overload, mitochondrial morphology change, and apoptotic response. Both conditions impaired NSC lineage progression. Ca 2+ mito homeostasis is influenced by Polo-mediated phosphorylation of a conserved residue in Miro, which positively regulates Miro localization to, and the integrity of, ERMCS. Our results elucidate a regulatory mechanism underlying Ca 2+ mito homeostasis and how its dysregulation may affect NSC metabolism/development and contribute to disease.