PNPASE Regulates RNA Import into Mitochondria

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2010 Aug 10

PMID 20691904

Citations 186

Authors

Geng Wang

Hsiao-Wen Chen

Yavuz Oktay

Jin Zhang

Eric L Allen

Geoffrey M Smith

Kelly C Fan

Jason S Hong

Samuel W French

J Michael McCaffery

Robert N Lightowlers

Herbert C Morse 3rd

Carla M Koehler

Michael A Teitell

Affiliations

Soon will be listed here.

Abstract

RNA import into mammalian mitochondria is considered essential for replication, transcription, and translation of the mitochondrial genome but the pathway(s) and factors that control this import are poorly understood. Previously, we localized polynucleotide phosphorylase (PNPASE), a 3' --> 5' exoribonuclease and poly-A polymerase, in the mitochondrial intermembrane space, a location lacking resident RNAs. Here, we show a new role for PNPASE in regulating the import of nuclear-encoded RNAs into the mitochondrial matrix. PNPASE reduction impaired mitochondrial RNA processing and polycistronic transcripts accumulated. Augmented import of RNase P, 5S rRNA, and MRP RNAs depended on PNPASE expression and PNPASE-imported RNA interactions were identified. PNPASE RNA processing and import activities were separable and a mitochondrial RNA targeting signal was isolated that enabled RNA import in a PNPASE-dependent manner. Combined, these data strongly support an unanticipated role for PNPASE in mediating the translocation of RNAs into mitochondria.

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References

Entelis N, Kolesnikova O, Martin R, Tarassov I . RNA delivery into mitochondria. Adv Drug Deliv Rev. 2001; 49(1-2):199-215. DOI: 10.1016/s0169-409x(01)00135-1. View

Kren B, Wong P, Sarver A, Zhang X, Zeng Y, Steer C . MicroRNAs identified in highly purified liver-derived mitochondria may play a role in apoptosis. RNA Biol. 2008; 6(1):65-72. PMC: 3972804. DOI: 10.4161/rna.6.1.7534. View

Rubio M, Rinehart J, Krett B, Duvezin-Caubet S, Reichert A, Soll D . Mammalian mitochondria have the innate ability to import tRNAs by a mechanism distinct from protein import. Proc Natl Acad Sci U S A. 2008; 105(27):9186-91. PMC: 2453747. DOI: 10.1073/pnas.0804283105. View

Mukherjee S, Basu S, Home P, Dhar G, Adhya S . Necessary and sufficient factors for the import of transfer RNA into the kinetoplast mitochondrion. EMBO Rep. 2007; 8(6):589-95. PMC: 2002530. DOI: 10.1038/sj.embor.7400979. View

Kolesnikova O, Entelis N, Jacquin-Becker C, Goltzene F, Chrzanowska-Lightowlers Z, Lightowlers R . Nuclear DNA-encoded tRNAs targeted into mitochondria can rescue a mitochondrial DNA mutation associated with the MERRF syndrome in cultured human cells. Hum Mol Genet. 2004; 13(20):2519-34. DOI: 10.1093/hmg/ddh267. View

Postic C, Magnuson M . DNA excision in liver by an albumin-Cre transgene occurs progressively with age. Genesis. 2000; 26(2):149-50. DOI: 10.1002/(sici)1526-968x(200002)26:2<149::aid-gene16>3.0.co;2-v. View

Portnoy V, Palnizky G, Yehudai-Resheff S, Glaser F, Schuster G . Analysis of the human polynucleotide phosphorylase (PNPase) reveals differences in RNA binding and response to phosphate compared to its bacterial and chloroplast counterparts. RNA. 2007; 14(2):297-309. PMC: 2212259. DOI: 10.1261/rna.698108. View

Stuart R, Koehler C . In vitro analysis of yeast mitochondrial protein import. Curr Protoc Cell Biol. 2008; Chapter 11:Unit 11.19. DOI: 10.1002/0471143030.cb1119s34. View

Hollingsworth M, Martin N . RNase P activity in the mitochondria of Saccharomyces cerevisiae depends on both mitochondrion and nucleus-encoded components. Mol Cell Biol. 1986; 6(4):1058-64. PMC: 367615. DOI: 10.1128/mcb.6.4.1058-1064.1986. View

10.

Doersen C, Altman S, Attardi G . Characterization of an RNase P activity from HeLa cell mitochondria. Comparison with the cytosol RNase P activity. J Biol Chem. 1985; 260(10):5942-9. View

11.

Alfonzo J, Soll D . Mitochondrial tRNA import--the challenge to understand has just begun. Biol Chem. 2009; 390(8):717-22. PMC: 4822550. DOI: 10.1515/BC.2009.101. View

12.

Diaz F, Garcia S, Hernandez D, Regev A, Rebelo A, Oca-Cossio J . Pathophysiology and fate of hepatocytes in a mouse model of mitochondrial hepatopathies. Gut. 2007; 57(2):232-42. PMC: 2730640. DOI: 10.1136/gut.2006.119180. View

13.

Yehudai-Resheff S, Schuster G . Characterization of the E.coli poly(A) polymerase: nucleotide specificity, RNA-binding affinities and RNA structure dependence. Nucleic Acids Res. 2000; 28(5):1139-44. PMC: 102612. DOI: 10.1093/nar/28.5.1139. View

14.

Koehler C, Jarosch E, Tokatlidis K, Schmid K, Schweyen R, Schatz G . Import of mitochondrial carriers mediated by essential proteins of the intermembrane space. Science. 1998; 279(5349):369-73. DOI: 10.1126/science.279.5349.369. View

15.

Chen H, Rainey R, Balatoni C, Dawson D, Troke J, Wasiak S . Mammalian polynucleotide phosphorylase is an intermembrane space RNase that maintains mitochondrial homeostasis. Mol Cell Biol. 2006; 26(22):8475-87. PMC: 1636764. DOI: 10.1128/MCB.01002-06. View

16.

Carpousis A . The Escherichia coli RNA degradosome: structure, function and relationship in other ribonucleolytic multienzyme complexes. Biochem Soc Trans. 2002; 30(2):150-5. View

17.

Claypool S, Oktay Y, Boontheung P, Loo J, Koehler C . Cardiolipin defines the interactome of the major ADP/ATP carrier protein of the mitochondrial inner membrane. J Cell Biol. 2008; 182(5):937-50. PMC: 2528576. DOI: 10.1083/jcb.200801152. View

18.

Symmons M, Jones G, Luisi B . A duplicated fold is the structural basis for polynucleotide phosphorylase catalytic activity, processivity, and regulation. Structure. 2000; 8(11):1215-26. DOI: 10.1016/s0969-2126(00)00521-9. View

19.

Walker S, Engelke D . A protein-only RNase P in human mitochondria. Cell. 2008; 135(3):412-4. PMC: 2803673. DOI: 10.1016/j.cell.2008.10.010. View

20.

Rainey R, Glavin J, Chen H, French S, Teitell M, Koehler C . A new function in translocation for the mitochondrial i-AAA protease Yme1: import of polynucleotide phosphorylase into the intermembrane space. Mol Cell Biol. 2006; 26(22):8488-97. PMC: 1636789. DOI: 10.1128/MCB.01006-06. View