A Spatial Atlas of Mitochondrial Gene Expression Reveals Dynamic Translation Hubs and Remodeling in Stress

Overview

Journal bioRxiv

Date 2024 Aug 16

PMID 39149346

Authors

Adam Begeman

John A Smolka

Ahmad Shami

Tejashree Pradip Waingankar

Samantha C Lewis

Affiliations

Soon will be listed here.

Abstract

Mitochondrial genome expression is important for cellular bioenergetics. How mitochondrial RNA processing and translation are spatially organized across dynamic mitochondrial networks is not well understood. Here, we report that processed mitochondrial RNAs are consolidated with mitoribosome components into translation hubs distal to either nucleoids or processing granules in human cells. During stress, these hubs are remodeled into translationally repressed mesoscale bodies containing messenger, ribosomal, and double-stranded RNA. We show that the highly conserved helicase SUV3 contributes to the distribution of processed RNA within mitochondrial networks, and that stress bodies form downstream of proteostatic stress in cells lacking SUV3 unwinding activity. We propose that the spatial organization of nascent chain synthesis into discrete domains serves to throttle the flow of genetic information in stress to ensure mitochondrial quality control.

References

Jourdain A, Koppen M, Wydro M, Rodley C, Lightowlers R, Chrzanowska-Lightowlers Z . GRSF1 regulates RNA processing in mitochondrial RNA granules. Cell Metab. 2013; 17(3):399-410. PMC: 3593211. DOI: 10.1016/j.cmet.2013.02.005. View

Wang G, Shimada E, Koehler C, Teitell M . PNPASE and RNA trafficking into mitochondria. Biochim Biophys Acta. 2011; 1819(9-10):998-1007. PMC: 3267854. DOI: 10.1016/j.bbagrm.2011.10.001. View

Tigano M, Vargas D, Tremblay-Belzile S, Fu Y, Sfeir A . Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance. Nature. 2021; 591(7850):477-481. DOI: 10.1038/s41586-021-03269-w. View

Zbinden A, Perez-Berlanga M, De Rossi P, Polymenidou M . Phase Separation and Neurodegenerative Diseases: A Disturbance in the Force. Dev Cell. 2020; 55(1):45-68. DOI: 10.1016/j.devcel.2020.09.014. View

Westermann B . Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol. 2010; 11(12):872-84. DOI: 10.1038/nrm3013. View

Ruan L, McNamara J, Zhang X, Chang A, Zhu J, Dong Y . Solid-phase inclusion as a mechanism for regulating unfolded proteins in the mitochondrial matrix. Sci Adv. 2020; 6(32):eabc7288. PMC: 7406381. DOI: 10.1126/sciadv.abc7288. View

Nakada K, Inoue K, Ono T, Isobe K, Ogura A, Goto Y . Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA. Nat Med. 2001; 7(8):934-40. DOI: 10.1038/90976. View

Dhir A, Dhir S, Borowski L, Jimenez L, Teitell M, Rotig A . Mitochondrial double-stranded RNA triggers antiviral signalling in humans. Nature. 2018; 560(7717):238-242. PMC: 6570621. DOI: 10.1038/s41586-018-0363-0. View

Ohkubo A, Van Haute L, Rudler D, Stentenbach M, Steiner F, Rackham O . The FASTK family proteins fine-tune mitochondrial RNA processing. PLoS Genet. 2021; 17(11):e1009873. PMC: 8601606. DOI: 10.1371/journal.pgen.1009873. View

10.

Ruzzenente B, Metodiev M, Wredenberg A, Bratic A, Park C, Camara Y . LRPPRC is necessary for polyadenylation and coordination of translation of mitochondrial mRNAs. EMBO J. 2011; 31(2):443-56. PMC: 3261557. DOI: 10.1038/emboj.2011.392. View

11.

Lavdovskaia E, Hanitsch E, Linden A, Pasen M, Challa V, Horokhovskyi Y . A roadmap for ribosome assembly in human mitochondria. Nat Struct Mol Biol. 2024; 31(12):1898-1908. PMC: 11638073. DOI: 10.1038/s41594-024-01356-w. View

12.

Spannl S, Tereshchenko M, Mastromarco G, Ihn S, Lee H . Biomolecular condensates in neurodegeneration and cancer. Traffic. 2019; 20(12):890-911. DOI: 10.1111/tra.12704. View

13.

Szczesny R, Borowski L, Malecki M, Wojcik M, Stepien P, Golik P . RNA degradation in yeast and human mitochondria. Biochim Biophys Acta. 2011; 1819(9-10):1027-34. DOI: 10.1016/j.bbagrm.2011.11.010. View

14.

Sharp P, Chakraborty A, Henninger J, Young R . RNA in formation and regulation of transcriptional condensates. RNA. 2021; 28(1):52-57. PMC: 8675292. DOI: 10.1261/rna.078997.121. View

15.

Krieger M, Abrahamian M, He K, Atamdede S, Hakimjavadi H, Momcilovic M . Trafficking of mitochondrial double-stranded RNA from mitochondria to the cytosol. Life Sci Alliance. 2024; 7(9. PMC: 11220484. DOI: 10.26508/lsa.202302396. View

16.

Jao C, Salic A . Exploring RNA transcription and turnover in vivo by using click chemistry. Proc Natl Acad Sci U S A. 2008; 105(41):15779-84. PMC: 2572917. DOI: 10.1073/pnas.0808480105. View

17.

Borowski L, Dziembowski A, Hejnowicz M, Stepien P, Szczesny R . Human mitochondrial RNA decay mediated by PNPase-hSuv3 complex takes place in distinct foci. Nucleic Acids Res. 2012; 41(2):1223-40. PMC: 3553951. DOI: 10.1093/nar/gks1130. View

18.

Hochberg I, Demain L, Richer J, Thompson K, Urquhart J, Rea A . Bi-allelic variants in the mitochondrial RNase P subunit PRORP cause mitochondrial tRNA processing defects and pleiotropic multisystem presentations. Am J Hum Genet. 2021; 108(11):2195-2204. PMC: 8595931. DOI: 10.1016/j.ajhg.2021.10.002. View

19.

Zorkau M, Albus C, Berlinguer-Palmini R, Chrzanowska-Lightowlers Z, Lightowlers R . High-resolution imaging reveals compartmentalization of mitochondrial protein synthesis in cultured human cells. Proc Natl Acad Sci U S A. 2021; 118(6). PMC: 8017971. DOI: 10.1073/pnas.2008778118. View

20.

McArthur K, Whitehead L, Heddleston J, Li L, Padman B, Oorschot V . BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science. 2018; 359(6378). DOI: 10.1126/science.aao6047. View