Lee Seongsoo, Lee Kyu-Sun, Huh Sungun, Liu Song, Lee Do-Yeon, Hong Seung Hyun, Yu Kweon, Lu Bingwei
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
BioNanotechnology Research Center, Korea Research Institute of Biotechnology and Bioscience, Daejeon, 305-806, Korea.
Dev Cell. 2016 Apr 18;37(2):174-189. doi: 10.1016/j.devcel.2016.03.023.
Mitochondria play central roles in buffering intracellular Ca²⁺ transients. While basal mitochondrial Ca²⁺ (Ca²⁺ mito) is needed to maintain organellar physiology, Ca²⁺ mito overload can lead to cell death. How Ca²⁺ 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 Ca²⁺ mito homeostasis control, independent of its role in mitochondrial transport. Miro interacts with Ca²⁺ transporters at the ER-mitochondria contact site (ERMCS). Its inactivation causes Ca²⁺ mito depletion and metabolic impairment, whereas its overexpression results in Ca²⁺ mito overload, mitochondrial morphology change, and apoptotic response. Both conditions impaired NSC lineage progression. Ca²⁺ 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 Ca²⁺ mito homeostasis and how its dysregulation may affect NSC metabolism/development and contribute to disease.
线粒体在缓冲细胞内钙离子瞬变中起核心作用。虽然基础线粒体钙离子（Ca²⁺mito）对于维持细胞器生理功能是必需的，但Ca²⁺mito过载会导致细胞死亡。目前对Ca²⁺mito稳态如何调节尚不清楚。在此，我们表明Miro是线粒体运输机制的一个已知组成部分，它通过控制Ca²⁺mito稳态来调节果蝇神经干细胞（NSC）的发育，这与其在线粒体运输中的作用无关。Miro在内质网-线粒体接触位点（ERMCS）与钙离子转运体相互作用。其失活会导致Ca²⁺mito耗竭和代谢受损，而其过表达则会导致Ca²⁺mito过载、线粒体形态改变和凋亡反应。这两种情况都会损害NSC谱系进展。Ca²⁺mito稳态受Polo介导的Miro中一个保守残基的磷酸化影响，该磷酸化正向调节Miro定位于ERMCS及其完整性。我们的结果阐明了Ca²⁺mito稳态的调控机制，以及其失调如何影响NSC代谢/发育并导致疾病。
