Polo Kinase Phosphorylates Miro to Control ER-Mitochondria Contact Sites and Mitochondrial Ca(2+) Homeostasis in Neural Stem Cell Development.
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.
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.
Seongsoo
S
Lee
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.
Kyu-Sun
KS
Lee
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Sungun
S
Huh
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Song
S
Liu
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Do-Yeon
DY
Lee
BioNanotechnology Research Center, Korea Research Institute of Biotechnology and Bioscience, Daejeon, 305-806, Korea.
Seung Hyun
SH
Hong
BioNanotechnology Research Center, Korea Research Institute of Biotechnology and Bioscience, Daejeon, 305-806, Korea.
Kweon
K
Yu
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Bingwei
B
Lu
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D029721:Drosophila Proteins; C072004:polo protein, Drosophila; D017346:Protein Serine-Threonine Kinases; C504427:Miro protein, Drosophila; D020741:rho GTP-Binding Proteins; D002118:Calcium