Trafficking of mitochondrial double-stranded RNA from mitochondria to the cytosol.

Autor: Krieger MR; Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, USA., Abrahamian M; Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, USA., He KL; Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, USA., Atamdede S; Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, USA., Hakimjavadi H; Department of Pathology, Children's Hospital Los Angeles, Los Angeles, CA, USA., Momcilovic M; Pulmonary and Critical Care Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA., Ostrow D; Department of Pathology, Children's Hospital Los Angeles, Los Angeles, CA, USA., Maggo SD; Department of Pathology, Children's Hospital Los Angeles, Los Angeles, CA, USA., Tsang YP; Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, USA., Gai X; Department of Pathology, Children's Hospital Los Angeles, Los Angeles, CA, USA.; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Chanfreau GF; Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, USA.; Molecular Biology Institute, UCLA, Los Angeles, CA, USA., Shackelford DB; Pulmonary and Critical Care Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA., Teitell MA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA.; Molecular Biology Institute, UCLA, Los Angeles, CA, USA.; Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA, USA.; Broad Stem Cell Research Center, UCLA, Los Angeles, CA, USA.; NanoSystems Institute, UCLA, Los Angeles, CA, USA., Koehler CM; Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, USA koehlerc@chem.ucla.edu.; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA.; Molecular Biology Institute, UCLA, Los Angeles, CA, USA.
Jazyk: angličtina
Zdroj: Life science alliance [Life Sci Alliance] 2024 Jul 02; Vol. 7 (9). Date of Electronic Publication: 2024 Jul 02 (Print Publication: 2024).
DOI: 10.26508/lsa.202302396
Abstrakt: In addition to mitochondrial DNA, mitochondrial double-stranded RNA (mtdsRNA) is exported from mitochondria. However, specific channels for RNA transport have not been demonstrated. Here, we begin to characterize channel candidates for mtdsRNA export from the mitochondrial matrix to the cytosol. Down-regulation of SUV3 resulted in the accumulation of mtdsRNAs in the matrix, whereas down-regulation of PNPase resulted in the export of mtdsRNAs to the cytosol. Targeting experiments show that PNPase functions in both the intermembrane space and matrix. Strand-specific sequencing of the double-stranded RNA confirms the mitochondrial origin. Inhibiting or down-regulating outer membrane proteins VDAC1/2 and BAK/BAX or inner membrane proteins PHB1/2 strongly attenuated the export of mtdsRNAs to the cytosol. The cytosolic mtdsRNAs subsequently localized to large granules containing the stress protein TIA-1 and activated the type 1 interferon stress response pathway. Abundant mtdsRNAs were detected in a subset of non-small-cell lung cancer cell lines that were glycolytic, indicating relevance in cancer biology. Thus, we propose that mtdsRNA is a new damage-associated molecular pattern that is exported from mitochondria in a regulated manner.
(© 2024 Krieger et al.)
Databáze: MEDLINE