RRC ID 65116
Author Matsui H, Ito J, Matsui N, Uechi T, Onodera O, Kakita A.
Title Cytosolic dsDNA of mitochondrial origin induces cytotoxicity and neurodegeneration in cellular and zebrafish models of Parkinson's disease.
Journal Nat Commun
Abstract Mitochondrial dysfunction and lysosomal dysfunction have been implicated in Parkinson's disease (PD), but the links between these dysfunctions in PD pathogenesis are still largely unknown. Here we report that cytosolic dsDNA of mitochondrial origin escaping from lysosomal degradation was shown to induce cytotoxicity in cultured cells and PD phenotypes in vivo. The depletion of PINK1, GBA and/or ATP13A2 causes increases in cytosolic dsDNA of mitochondrial origin and induces type I interferon (IFN) responses and cell death in cultured cell lines. These phenotypes are rescued by the overexpression of DNase II, a lysosomal DNase that degrades discarded mitochondrial DNA, or the depletion of IFI16, which acts as a sensor for cytosolic dsDNA of mitochondrial origin. Reducing the abundance of cytosolic dsDNA by overexpressing human DNase II ameliorates movement disorders and dopaminergic cell loss in gba mutant PD model zebrafish. Furthermore, IFI16 and cytosolic dsDNA puncta of mitochondrial origin accumulate in the brain of patients with PD. These results support a common causative role for the cytosolic leakage of mitochondrial DNA in PD pathogenesis.
Volume 12(1)
Pages 3101
Published 2021-5-25
DOI 10.1038/s41467-021-23452-x
PII 10.1038/s41467-021-23452-x
PMID 34035300
PMC PMC8149644
MeSH Animals Animals, Genetically Modified Brain / metabolism Brain / pathology Brain / ultrastructure Cell Line, Tumor Cell Survival / genetics Cytosol / metabolism DNA / genetics* DNA / metabolism Disease Models, Animal* Endodeoxyribonucleases / genetics Endodeoxyribonucleases / metabolism HEK293 Cells HeLa Cells Humans Microscopy, Electron Mitochondria / genetics* Mitochondria / metabolism Parkinson Disease / genetics* Parkinson Disease / metabolism Protein Serine-Threonine Kinases / genetics Protein Serine-Threonine Kinases / metabolism Zebrafish / genetics* Zebrafish / metabolism
IF 12.121
Human and Animal Cells 293T(RCB2202)