PNPASE and RNA trafficking into mitochondria

Wang, Geng; Shimada, Eriko; Koehler, Carla M.; Teitell, Michael A.

doi:10.1016/j.bbagrm.2011.10.001

Cited by 84Mitochondrial Function and PathologyAutophagy in Disease and TherapyNuclear Structure and Function

PNPASE and RNA trafficking into mitochondria

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Wang, Geng, Shimada, Eriko, Koehler, Carla M., Teitell, Michael A.·2012·Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms

DOI 10.1016/j.bbagrm.2011.10.001PMC PMC3267854

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Abstract

The mitochondrial genome encodes a very small fraction of the macromolecular components that are required to generate functional mitochondria. Therefore, most components are encoded within the nuclear genome and are imported into mitochondria from the cytosol. Understanding how mitochondria are assembled, function, and dysfunction in diseases requires detailed knowledge of mitochondrial import mechanisms and pathways. The import of nucleus-encoded RNAs is required for mitochondrial biogenesis and function, but unlike pre-protein import, the pathways and cellular machineries of RNA import are poorly defined, especially in mammals. Recent studies have shown that mammalian polynucleotide phosphorylase (PNPASE) localizes in the mitochondrial intermembrane space (IMS) to regulate the import of RNA. The identification of PNPASE as the first component of the RNA import pathway, along with a growing list of nucleus-encoded RNAs that are imported and newly developed assay systems for RNA import studies, suggest a unique opportunity is emerging to identify the factors and mechanisms that regulate RNA import into mammalian mitochondria. Here we summarize what is known in this fascinating area of mitochondrial biogenesis, identify areas that require further investigation, and speculate on the impact unraveling RNA import mechanisms and pathways will have for the field going forward. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.

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PNPASE orchestrates the import of specific nucleus-encoded RNAs into mitochondria through recognition of distinct RNA stem-loop structures.
“PNPASE orchestrates the import of specific nucleus-encoded RNAs into the mitochondria through its recognition of distinct RNA stem-loop structures”
From The mitochondrial long non-coding RNA lncMtloop regulates mitochondrial transcription and suppresses Alzheimer’s disease (2024) · cites this paper as Wang et al, 2012a
Section 5.3 reports PNPASE-dependent import of specific nucleus-encoded RNAs and describes stem-loop-forming sequences in RNase P and MRP RNAs. The paper says stem-loops may facilitate PNPASE binding, but states that the mechanism linking recognition to import remains unclear; the claim presents that mechanism as established. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
PNPASE is a key player in the RNA import machinery of mammalian mitochondria.
“PNPASE emerged as a key player in the RNA import machinery of mammalian mitochondria (Wang et al, 2010; Wang et al, 2012a).”
From The mitochondrial long non-coding RNA lncMtloop regulates mitochondrial transcription and suppresses Alzheimer’s disease (2024) · cites this paper as Wang et al, 2012a

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PNPase activity determines the efficiency of mRNA 3′‐end processing, the degradation of tRNA and the extent of polyadenylation in chloroplasts
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“Subcellular localization of PNPASE Mammalian PNPASE has an amino-terminal MTS and has been localized to mitochondria in both immunofluorescence and cell-fractionation studies [32, 44, 45].”
BackgroundInfluential
The role of 3'-5' exoribonucleases in RNA degradation.
Andrade, J. M., Pobre, V., Silva, I. J., Domingues, S., & Arraiano, C. (2009) · Progress in Molecular Biology and Translational Science · doi:10.1016/s0079-6603(08)00805-2 · Cited by 118 · see citing works
Biological significance of 5S rRNA import into human mitochondria: role of ribosomal protein MRP-L18.Preprint
Smirnov, A., Entelis, N., Martin, R., & Tarassov, I. (2011) · Genes & Development · doi:10.1101/gad.624711 · Cited by 117 · cited 5× · see citing works
“Smirnov A, Entelis N, Martin RP, Tarassov I. Biological significance of 5S rRNA import into human mitochondria: role of ribosomal protein MRP-L18.”
BackgroundInfluential
Identification and cloning of human polynucleotide phosphorylase, hPNPase old-35 , in the context of terminal differentiation and cellular senescence
Leszczyniecka, M., Kang, D., Sarkar, D., Su, Z.-Z., Holmes, M., Valerie, K. C., & Fisher, P. B. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.252643699 · Cited by 116 · see citing works
A New Function in Translocation for the Mitochondrial i-AAA Protease Yme1: Import of Polynucleotide Phosphorylase into the Intermembrane Space
Rainey, R. N., Glavin, J. D., Chen, H.-W., French, S., Teitell, M., & Koehler, C. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.01006-06 · Cited by 116 · cited 3× · see citing works
“imported and processed PNPASE then assembles into a functional homo-oligomeric complex, consisting of a trimer or a dimer of trimers [44].”
BackgroundSelf-citation
Saccharomyces cerevisiae imports the cytosolic pathway for Gln‐tRNA synthesis into the mitochondrionPreprint
Krett, B., Rinehart, J., Rubio, M. A. T., Alfonzo, J. D., & Söll, D. (2005) · Genes & Development · doi:10.1101/gad.1269305 · Cited by 114 · cited 1× · see citing works
“Yeast tRNAGln is also imported into isolated yeast mitochondria without requiring added cytosolic factors [100].”
Background
5 S rRNA and tRNA Import into Human Mitochondria
Entelis, N., Kolesnikova, O., Dogan, S., Martin, R. P., & Tarassov, I. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m103906200 · Cited by 113 · cited 3× · see citing works
“Additional nucleus-encoded small RNA molecules are also present in mammalian mitochondria [54, 62-65].”
Background
Investigation of a pathogenic mtDNA microdeletion reveals a translation-dependent deadenylation decay pathway in human mitochondria.
Temperley, R., Seneca, S., Tońska, K., Bartnik, E., Bindoff, L., Lightowlers, R., & Chrzanowska-Lightowlers, Z. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg238 · Cited by 110 · cited 1× · see citing works
“Detection and isolation of truncated, non-abundant, polyadenylated mitochondrial RNAs suggests that polyadenylation could occur with RNA transcripts destined for degradation, whereas another study shows deadenylation sometimes leads to quick decay of certain mutant transcripts [107,108].”
Background
Human Mitochondrial SUV3 and Polynucleotide Phosphorylase Form a 330-kDa Heteropentamer to Cooperatively Degrade Double-stranded RNA with a 3′-to-5′ Directionality*
Wang, D., Shu, Z., Lieser, S. A., Chen, P.-L., & Lee, W.-H. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.009605 · Cited by 109 · cited 2× · see citing works
“PNPASE was reported to interact with hSUV3, but this would place PNPASE in the mitochondrial matrix [47].”
Background
Crystal structure of Escherichia coli PNPase: central channel residues are involved in processive RNA degradation.
Shi, Z., Yang, W.-Z., Lin-Chao, S., Chak, K., & Yuan, H. S. (2008) · RNA: A publication of the RNA Society · doi:10.1261/rna.1244308 · Cited by 109 · cited 3×
“RNase PH domains [37,41].”
BackgroundInfluential
Immunolocalization of 7-2-ribonucleoprotein in the granular component of the nucleolus.
Reimer, G., Raška, I., Scheer, U., & Tan, E. M. (1988) · Experimental Cell Research · doi:10.1016/0014-4827(88)90126-7 · Cited by 108 · cited 1× · see citing works
“Most RNase MRP, however, resides in the nucleus [77, 78].”
Background
RNA Polyadenylation and Degradation in Cyanobacteria Are Similar to the Chloroplast but Different from Escherichia coli *
Rott, R., Zipor, G., Portnoy, V., Liveanu, V., & Schuster, G. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211571200 · Cited by 104 · cited 1× · see citing works
“Prokaryotic and plant PNPASE function in RNA quality control through its RNA polymerase and degradation activities [22-26].”
Background
RNase P activity in the mitochondria of Saccharomyces cerevisiae depends on both mitochondrion and nucleus-encoded components
Hollingsworth, M. J., & Martin, N. C. (1986) · Molecular and Cellular Biology · doi:10.1128/mcb.6.4.1058-1064.1986 · Cited by 103 · cited 1× · see citing works
“cerevisiae is encoded within its mtDNA [86].”
The Single Mitochondrial Porin of Trypanosoma brucei is the Main Metabolite Transporter in the Outer Mitochondrial Membrane
Pusnik, M., Charrière, F., Mäser, P., Waller, R. F., Dagley, M. J., Lithgow, T. J., & Schneider, A. (2008) · Molecular Biology and Evolution · doi:10.1093/molbev/msn288 · Cited by 102 · see citing works
Protein-protein interactions between human exosome components support the assembly of RNase PH-type subunits into a six-membered PNPase-like ring.
Raijmakers, R., Egberts, W. V., van Venrooij, W. V., & Pruijn, G. (2002) · Journal of Molecular Biology · doi:10.1016/s0022-2836(02)00947-6 · Cited by 99 · cited 2×
“Interestingly, the archaeal and eukaryotic exosomes, which do not contain PNPASE but also function in RNA turnover and surveillance, have a similar trimeric doughnut-shaped quaternary structure [12,20].”
Background
Mitochondrial Enzyme Rhodanese Is Essential for 5 S Ribosomal RNA Import into Human Mitochondria*
Smirnov, A., Comte, C., Mager-Heckel, A., Addis, V., Krasheninnikov, I., Martin, R., Entelis, N., & Tarassov, I. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.151183 · Cited by 98 · cited 3× · see citing works
“Misfolded rhodanese then binds to the 5S rRNA and the combination acts as reciprocal chaperones to facilitate import [101].”
Background
Stable PNPase RNAi silencing: its effect on the processing and adenylation of human mitochondrial RNA.
Slomovic, S., & Schuster, G. (2007) · RNA: A publication of the RNA Society · doi:10.1261/rna.697308 · Cited by 95 · cited 6× · see citing works
“Also, the effect that PNPT1 knockdown and ATP depletion had on mtRNA poly(A) tail lengths appears distinct, with the latter causing a decrease in poly(A) tail lengths in ND3 and ND5 mtRNA transcripts compared to an increase in poly(A) tail lengths by PNPT1 knockdown [110].”
BackgroundInfluential
Mitochondrial tRNA import – the challenge to understand has just begun
Alfonzo, J. D., & Söll, D. (2009) · Biological chemistry · doi:10.1515/bc.2009.101 · Cited by 94 · cited 1×
“3) [72].”
Characterization of the E.coli poly(A) polymerase: nucleotide specificity, RNA-binding affinities and RNA structure dependence.
Yehudai-Resheff, S., & Schuster, G. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.5.1139 · Cited by 94 · cited 1× · see citing works
“RNA structural elements regulate PNPASE functions in chloroplasts and prokaryotes and a stem-loop structure protects RNAs from degradation by chloroplast PNPASE [23, 57, 58].”
Background
Mutational analysis of polynucleotide phosphorylase from Escherichia coli.
Jarrige, A., Bréchemier-Baey, D., Mathy, N., Duché, O., & Portier, C. (2002) · Journal of Molecular Biology · doi:10.1016/s0022-2836(02)00645-9 · Cited by 92 · cited 1×
“Prokaryotic and plant PNPASE function in RNA quality control through its RNA polymerase and degradation activities [22-26].”
Background
Evidence for an adaptation mechanism of mitochondrial translation via tRNA import from the cytosol.
Kamenski, P., Kolesnikova, O., Jubenot, V., Entelis, N., Krasheninnikov, I., Martin, R., & Tarassov, I. (2007) · Molecules and Cells · doi:10.1016/j.molcel.2007.04.019 · Cited by 91 · cited 1× · see citing works
“Mitochondrial import of nucleus-encoded RNAs including tRNAs , 5S rRNA, RNase P RNA, and MRP RNA is essential for mitochondrial DNA replication, transcription and translation [3, 5-10].”
Background
Human polynucleotide phosphorylase, hPNPase, is localized in mitochondria.
Piwowarski, J., Grzechnik, P., Dziembowski, A., Dmochowska, A., Minczuk, M., & Stepien, P. (2003) · Journal of Molecular Biology · doi:10.1016/s0022-2836(03)00528-x · Cited by 87 · cited 1× · see citing works
“Mammalian PNPASE has an amino-terminal MTS and has been localized to mitochondria in both immunofluorescence and cell-fractionation studies [32, 44, 45].”
Background
Polyadenylation creates the discriminator nucleotide of chicken mitochondrial tRNA(Tyr).
Yokobori, S., & Pääbo, S. (1997) · Journal of Molecular Biology · doi:10.1006/jmbi.1996.0728 · Cited by 82 · cited 1×
“RNA cleavage occurs at the 3′ and 5′ ends of the tRNAs that intervene between RNA coding genes, followed by polyadenylation of mtRNAs [104-106].”
Background
RNA delivery into mitochondria.
Entelis, N., Kolesnikova, O., Martin, R., & Tarassov, I. (2001) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(01)00135-1 · Cited by 78 · cited 1× · see citing works
“Most non-coding RNAs that function in mitochondria are encoded within the mtDNA [59].”
Background
Sweating the small stuff: microRNA discovery in plants.
Meyers, B., Souret, F., Lu, C., & Green, P. (2006) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2006.01.008 · Cited by 77 · cited 1×
“miRNAs are a class of small (~22 ribonucleotide) non-coding RNAs that regulate gene expression post-transcriptionally by binding to imperfectly or perfectly matched complementary sequences at the 3′ end of target mRNAs, usually resulting in translational repression or transcript degradation and gene silencing [91, 92].”
Background
Opposing Effects of Polyadenylation on the Stability of Edited and Unedited Mitochondrial RNAs in Trypanosoma brucei
Kao, C.-Y., & Read, L. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.5.1634-1644.2005 · Cited by 74 · cited 1×
“PNPASE is a highly conserved 3′-5′ exoribonuclease expressed in organisms that include bacteria, plants, flies, mice, and humans, but is absent in fungi, Trypanosoma, and Archaea [12-16].”
Background
Function of the Conserved S1 and KH Domains in Polynucleotide Phosphorylase
Stickney, L. M., Hankins, J. S., Miao, X., & Mackie, G. (2005) · Journal of Bacteriology · doi:10.1128/jb.187.21.7214-7221.2005 · Cited by 73 · cited 1× · see citing works
“And KH and S1 RNA binding domains, which are also present in other RNA binding proteins, are located at the PNPASE carboxy-terminus [37-39].”
Background
Domain Analysis of the Chloroplast Polynucleotide Phosphorylase Reveals Discrete Functions in RNA Degradation, Polyadenylation, and Sequence Homology with Exosome Proteins Article, publication date, and citation information can be found at www.plantcell.org/cgi/doi/10.1105/tpc.013326.
Yehudai-Resheff, S., Portnoy, V., Yogev, S., Adir, N., & Schuster, G. (2003) · The Plant Cell Online · doi:10.1105/tpc.013326 · Cited by 72 · cited 6×
“Subcellular localization of PNPASE Mammalian PNPASE has an amino-terminal MTS and has been localized to mitochondria in both immunofluorescence and cell-fractionation studies [32, 44, 45].”
BackgroundInfluential
Human polynucleotide phosphorylase protein in response to oxidative stress.
Hayakawa, H., & Sekiguchi, M. (2006) · Biochemistry · doi:10.1021/bi052585l · Cited by 70 · cited 1× · see citing works
“By contrast, other studies showed abundant PNPASE expression in human cell lines under basal conditions [32-34] with IFNβ exposure failing to induce further expression in some of the lines examined [32, 33].”
Result
RNA editing in the acceptor stem of squid mitochondrial tRNA(Tyr).
Tomita, K., Ueda, T., & Watanabe, K. (1996) · Nucleic Acids Research · doi:10.1093/nar/24.24.4987 · Cited by 70 · cited 1×
“RNA cleavage occurs at the 3′ and 5′ ends of the tRNAs that intervene between RNA coding genes, followed by polyadenylation of mtRNAs [104–106].”
Background
A yeast mitochondrial presequence functions as a signal for targeting to plant mitochondria in vivo.
Schmitz, U., & Lonsdale, D. M. (1989) · The Plant Cell · doi:10.1105/tpc.1.8.783 · Cited by 70 · cited 2×
“In addition, the metabolic enzyme enolase helps to deliver a tRNA/ synthetase complex to the import machinery [69-71].”
Background
The PNPase, exosome and RNA helicases as the building components of evolutionarily-conserved RNA degradation machines.
Lin-Chao, S., Chiou, N.-T., & Schuster, G. (2007) · Journal of Biomedical Sciences · doi:10.1007/s11373-007-9178-y · Cited by 69 · cited 2× · see citing works
“PNPASE degrades RNA by phosphorolysis and can also function as a template independent polymerase [17-23].”
Background
The regulatory function of poly(A) and adjacent 3' sequences in translated RNA.
Littauer, U., & Soreq, H. (1982) · Progress in Nucleic Acid Research and Molecular Biology · doi:10.1016/s0079-6603(08)60597-8 · Cited by 69 · cited 1×
“independent polymerase [17–23].”
The origin of polynucleotide phosphorylase domains.
Leszczyniecka, M., DeSalle, R., Kang, D., & Fisher, P. B. (2004) · Molecular Phylogenetics and Evolution · doi:10.1016/j.ympev.2003.07.012 · Cited by 68 · cited 2×
“PNPASE is a highly conserved 3′-5′ exoribonuclease expressed in organisms that include bacteria, plants, flies, mice, and humans, but is absent in fungi, Trypanosoma, and Archaea [12-16].”
Background
Two distinct structural elements of 5S rRNA are needed for its import into human mitochondria.
Smirnov, A., Tarassov, I., Mager-Heckel, A., Letzelter, M., Martin, R., Krasheninnikov, I., & Entelis, N. (2008) · RNA: A publication of the RNA Society · doi:10.1261/rna.952208 · Cited by 67 · cited 1× · see citing works
“the proximal part of helix 1 containing a conserved uncompensated G:U pair, and the second is associated with the loop E-helix IV region with several non-canonical structural features [87, 102].”
Background
Elongation factor 1a mediates the specificity of mitochondrial tRNA import in T. brucei
Bouzaidi-Tiali, N., Aeby, E., Charrière, F., Pusnik, M., & Schneider, A. (2007) · EMBO Journal · doi:10.1038/sj.emboj.7601857 · Cited by 67
Defining the Domains of Human Polynucleotide Phosphorylase (hPNPaseOLD-35) Mediating Cellular Senescence
Sarkar, D., Park, E., Emdad, L., Randolph, A., Valerie, K., & Fisher, P. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.16.7333-7343.2005 · Cited by 63 · cited 2× · see citing works
“In one set of human cell line studies, PNPASE was not detectable without IFNβ induction [30, 31].”
Background
Expression regulation and genomic organization of human polynucleotide phosphorylase, hPNPase(old-35), a Type I interferon inducible early response gene.
Leszczyniecka, M., Su, Z.-Z., Kang, D., Sarkar, D., & Fisher, P. (2003) · Gene · doi:10.1016/s0378-1119(03)00752-2 · Cited by 61 · see citing works
Analysis of the human polynucleotide phosphorylase (PNPase) reveals differences in RNA binding and response to phosphate compared to its bacterial and chloroplast counterparts.
Portnoy, V., Palnizky, G., Yehudai-Resheff, S., Glaser, F., & Schuster, G. (2007) · RNA: A publication of the RNA Society · doi:10.1261/rna.698108 · Cited by 57 · cited 3× · see citing works
“Recombinant mammalian PNPASE does not preferentially bind poly(A) containing RNAs, consistent with data that PNPASE does not metabolize poly(A) mRNA tails [103].”
BackgroundInfluential
Import of Nuclear DNA-Encoded RNAs into Mitochondria and Mitochondrial Translation
Tarassov, I., Kamenski, P., Kolesnikova, O., Karicheva, O., Martin, R., Krasheninnikov, I., & Entelis, N. (2007) · Cell Cycle · doi:10.4161/cc.6.20.4783 · Cited by 55 · cited 1× · see citing works
“Mitochondrial import of nucleus-encoded RNAs including tRNAs , 5S rRNA, RNase P RNA, and MRP RNA is essential for mitochondrial DNA replication, transcription and translation [3, 5-10].”
Background
Mitochondrial RNA Import
Sieber, F., Duchêne, A., & Maréchal‐Drouard, L. (2011) · International review of cytology · doi:10.1016/b978-0-12-386043-9.00004-9 · Cited by 54 · cited 1× · see citing works
“Compared to the mitochondrial protein import pathways, which have beenwell characterized [1–4], the pathways importing RNAs into mammalian mitochondria, and the functions of imported RNAs, are just being discovered.”
Background
Polynucleotide phosphorylase: An evolutionary conserved gene with an expanding repertoire of functions
Sarkar, D., & Fisher, P. B. (2006) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2006.04.003 · Cited by 53 · cited 2× · see citing works
“PNPASE is a highly conserved 3′-5′ exoribonuclease expressed in organisms that include bacteria, plants, flies, mice, and humans, but is absent in fungi, Trypanosoma, and Archaea [12-16].”
Background
Defining the mechanism by which IFN-β dowregulates c-myc expression in human melanoma cells: pivotal role for human polynucleotide phosphorylase (hPNPaseold-35)
Sarkar, D., Park, E., & Fisher, P. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401829 · Cited by 53
Characterization of target genes at the 2p15–16 amplicon in diffuse large B‐cell lymphoma
Fukuhara, N., Tagawa, H., Kameoka, Y., Kasugai, Y., Karnan, S., Kameoka, J., Sasaki, T., Morishima, Y., Nakamura, S., & Seto, M. (2006) · Cancer Science · doi:10.1111/j.1349-7006.2006.00209.x · Cited by 50 · cited 1×
“This genomic region shows deletions and amplifications in human B cell lymphoma and in several genetic disorders [28, 29].”
Background
Polyadenylation in mammalian mitochondria: insights from recent studies.
Nagaike, T., Suzuki, T., & Ueda, T. (2008) · Biochimica et Biophysica Acta · doi:10.1016/j.bbagrm.2008.02.001 · Cited by 47 · cited 1× · see citing works
“In bacteria, organelles, and some eukaryotes, polyadenylation is catalyzed by one of the poly(A) polymerases (PAPs) or PNPASE [109].”
Background
Specific features of 5S rRNA structure — Its interactions with macromolecules and possible functions
Smirnov, A., Entelis, N., Krasheninnikov, I. A., Martin, R. P., & Tarassov, I. (2008) · Biochemistry (Moscow) · doi:10.1134/s000629790813004x · Cited by 44 · cited 2× · see citing works
“the proximal part of helix 1 containing a conserved uncompensated G:U pair, and the second is associated with the loop E-helix IV region with several non-canonical structural features [87, 102].”
Background
Modulating T cell signals using CD3/CD28 Xcyte™ Dynabeads® allows for selective expansion or deletion of antigen-specific T cells
Sarkar, D., Lebedeva, I., Emdad, L., Kang, D., Baldwin, A., & Fisher, P. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1772 · Cited by 41 · see citing works
Comparison of mitochondrial and nucleolar RNase MRP reveals identical RNA components with distinct enzymatic activities and protein components.
Lu, Q.-S., Wierzbicki, S., Krasilnikov, A. S., & Schmitt, M. (2010) · RNA: A publication of the RNA Society · doi:10.1261/rna.1893710 · Cited by 40 · cited 1× · see citing works
“cerevisiae mitochondrial and nuclear RNase MRP have identical RNA components but contain distinct protein components and show differing enzymatic activities [84].”
Background
Mitochondrial import of a yeast cytoplasmic tRNALys: possible roles of aminoacylation and modified nucleosides in subcellular partitioning
Entelis, N., Krasheninnikov, I. A., Martin, R., & Tarassov, I. (1996) · FEBS Letters · doi:10.1016/0014-5793(96)00259-1 · Cited by 33 · cited 2×
“As already mentioned, nucleus-encoded tRNACUU Lys is imported into isolated yeast mitochondria in vitro [67,68] with tRNA synthetase binding, aminoacylation [69,70] and help from cytosolic enolase [71].”
Background
Genomic mapping of chromosomal region 2p15-p21 (D2S378-D2S391): integration of Genemap'98 within a framework of yeast and bacterial artificial chromosomes.
Kirschner, L. S., Taymans, S. E., Pack, S. D., Pak, E., Pike, B. L., Chandrasekharappa, S., Zhuang, Z.-P., & Stratakis, C. A. (1999) · Genomics · doi:10.1006/geno.1999.5957 · Cited by 30 · cited 1×
“This genomic region shows deletions and amplifications in human B cell lymphoma and in several genetic disorders [28, 29].”
Background
Coexistence of nuclear DNA-encoded tRNAVal(AAC) and mitochondrial DNA-encoded tRNAVal(UAC) in mitochondria of a liverwort Marchantia polymorpha.
Akashi, K., Takenaka, M., Yamaoka, S., Suyama, Y., Fukuzawa, H., & Ohyama, K. (1998) · Nucleic Acids Research · doi:10.1093/nar/26.9.2168 · Cited by 30 · cited 1×
“And for Saccharomyces cerevisiae and Marchantia polymorpha, the mtDNA encodes a set of tRNAs that is sufficient for translating all mtRNA codons, but nucleus-encoded tRNAs are nevertheless imported for unknown reasons [60, 61].”
Background
The TCL1 oncoprotein binds the RNase PH domains of the PNPase exoribonuclease without affecting its RNA degrading activity.
French, S., Dawson, D. W., Chen, H.-W., Rainey, R. N., Sievers, S., Balatoni, C. E., Wong, L., Troke, J. J., Nguyen, M. T. N., Koehler, C., et al. (2007) · Cancer Letters · doi:10.1016/j.canlet.2006.07.006 · Cited by 26 · cited 1×
“PNPASE has also been reported as an interacting partner for TCL1, a cytosol-localized nonenzymatic oncoprotein that promotes B- and T-cell malignancies, and as a weak binding partner for hSUV3, a mitochondrial matrix RNA helicase [46, 47].”
BackgroundSelf-citation
A 5 S rRNA gene is present in the mitochondrial genome of the protist Reclinomonas americana but is absent from red algal mitochondrial DNA.
Lang, B., Goff, L. J., & Gray, M. W. (1996) · Journal of Molecular Biology · doi:10.1006/jmbi.1996.0486 · Cited by 26 · cited 2×
“Recent studies suggest that 5S rRNA is a component of the mitochondrial ribosome, but based on prior structural analysis of the mitochondrial ribosome its role could be very different from its cytosolic counterpart [7,89,90].”
Background
Changes in the conformation of 5S rRNA cause alterations in principal functions of the ribosomal nanomachine
Kouvela, E., Gerbanas, G. V., Xaplanteri, M., Petropoulos, A., Dinos, G., & Kalpaxis, D. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm546 · Cited by 20 · cited 1× · see citing works
“The 5S rRNA is the most abundant imported mammalian RNA and an essential ribosome component in almost all living organisms, providing regulatory interactions among most functional sites within the translating ribosomal machinery [88].”
Background
Up-regulation of human PNPase mRNA by beta-interferon has no effect on protein level in melanoma cell lines.
Gewartowski, K., Tomecki, R., Muchowski, L., Dmochowska, A., Dzwonek, A., Malecki, M., Skurzak, H., Ostrowski, J., & Stepien, P. (2006) · Acta Biochimica Polonica · doi:10.18388/abp.2006_3376 · Cited by 12 · cited 1×
“By contrast, other studies showed abundant PNPASE expression in human cell lines under basal conditions [32-34] with IFNβ exposure failing to induce further expression in some of the lines examined [32, 33].”
Result

Flagged first, then by citations

10 of the 122 references couldn’t be matched to a known paper.

Research works printed but not linked: 8

[9]Robertson HD Altman S Smith JD Purification and properties of a specific Escherichia coli ribonuclease which cleaves a tyrosine transfer ribonucleic acid presursor The Journal of biological chemistry 1972 247 5243 5251 4560501
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[43]Baginsky S Shteiman-Kotler A Liveanu V Yehudai-Resheff S Bellaoui M Settlage RE Shabanowitz J Hunt DF Schuster G Gruissem W Chloroplast PNPase exists as a homo-multimer enzyme complex that is distinct from the Escherichia coli degradosome RNA (New York, N.Y 2001 7 1464 1475 PMC1370190 11680851
[49]Sarkar D Lebedeva IV Emdad L Kang DC Baldwin AS Jr. Fisher PB Human polynucleotide phosphorylase (hPNPaseold-35): a potential link between aging and inflammation Cancer research 2004 64 7473 7478 15492272
[51]Finkel T Holbrook NJ Oxidants, oxidative stress and the biology of ageing Nature 2000 408 239 247 11089981
[82]Cai T Aulds J Gill T Cerio M Schmitt ME The Saccharomyces cerevisiae RNase mitochondrial RNA processing is critical for cell cycle progression at the end of mitosis Genetics 2002 161 1029 1042 12136008 PMC1462176
[91]Filipowicz W Bhattacharyya SN Sonenberg N Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nature reviews 2008 9 102 114 18197166
[116]Paradies G Ruggiero FM Petrosillo G Quagliariello E Age-dependent impairment of mitochondrial function in rat heart tissue. Effect of pharmacological agents Annals of the New York Academy of Sciences 1996 786 252 263 8687026

Sorted by citations

Correcting human mitochondrial mutations with targeted RNA import
Wang, G., Shimada, E., Zhang, J., Hong, J. S., Smith, G. M., Teitell, M. A., & Koehler, C. M. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1116792109 · Cited by 131 · see citing works
“And the mammalian polynucleotide phosphorylase (PNPASE) enzyme localizes to the mitochondrial intermembrane space (18–20) where it may function as an RNA receptor to augment translocation of RNAs into the mitochondrial matrix (6, 21).”
BackgroundSelf-citation
The post-transcriptional life of mammalian mitochondrial RNA
Rorbach, J., & Minczuk, M. (2012) · Biochemical Journal · doi:10.1042/bj20112208 · Cited by 118 · see citing works
Long noncoding RNAs coordinate functions between mitochondria and the nucleus
Dong, Y., Yoshitomi, T., Hu, J., & Cui, J. (2017) · Epigenetics & Chromatin · doi:10.1186/s13072-017-0149-x · Cited by 122 · see citing works
“Mammalian PNPASE may function as an RNA receptor to augment translocation of RNAs [55].”
BackgroundInfluential
Spectrum of combined respiratory chain defects
Mayr, J., Haack, T., Freisinger, P., Karall, D., Makowski, C., Koch, J., Feichtinger, R., Zimmermann, F., Rolinski, B., Ahting, U., et al. (2015) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-015-9831-y · Cited by 114 · see citing works
“…of PNPT1, polyribonucleotide nucleotidyltransferase 1, is still a matter of debate, but it might be involved in mitochondrial RNase P RNA import (Wang et al 2012) or part of mitochondrial RNA surveillance (Sarkar and Fisher 2006); mutations result in combined respiratory chain deficiency…”
Background
Mitochondria: one of the destinations of miRNAs.
Sripada, L., Tomar, D., & Singh, R. (2012) · Mitochondrion (Amsterdam. Print) · doi:10.1016/j.mito.2012.10.009 · Cited by 102
A mutation in PNPT1, encoding mitochondrial-RNA-import protein PNPase, causes hereditary hearing loss.
von Ameln, S., Wang, G., Boulouiz, R., Rutherford, M., Smith, G. M., Li, Y., Pogoda, H.-M., Nürnberg, G., Stiller, B., Volk, A., et al. (2012) · American Journal of Human Genetics · doi:10.1016/j.ajhg.2012.09.002 · Cited by 99 · see citing works
Self-citation
ATAD3 proteins: brokers of a mitochondria–endoplasmic reticulum connection in mammalian cells
Baudier, J. (2018) · Biological Reviews · doi:10.1111/brv.12373 · Cited by 99 · see citing works
“By tethering mitochondria to MAM and interaction with RNA, ATAD3A could function in the import of newly synthesised proteins and RNAs required for the biogenesis of mitochondrial ribosomes, and in translation and nucleoid maintenance in mammalian cells (Wang et al., 2012).”
Background
Adapting CRISPR/Cas9 System for Targeting Mitochondrial Genome
Hussain, S.-R. A., Yalvaç, M., Khoo, B. S., Eckardt, S., & McLaughlin, K. (2020) · bioRxiv · doi:10.3389/fgene.2021.627050 · Cited by 97 · see citing works
“One approach to deliver nuclear-encoded RNA into the mitochondria involves the utilization of a native RNA transport enzyme, polynucleotide phosphorylase (PNPase) encoded by PNPT1 gene, located in the mitochondrial intermembranous space (Wang et al., 2012).”
Background
Mitochondria, Telomeres and Telomerase Subunits
Zheng, Q., Huang, J., & Wang, G. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00274 · Cited by 110 · see citing works
“It is well known now that the theory is oversimplified and is only part of the story, as ROS may also activate compensatory pathways that may negate their deleterious effects (Yee et al., 2014; Wang and Hekimi, 2015).”
BackgroundSelf-citation
Exploring the mitochondrial microRNA import pathway through Polynucleotide Phosphorylase (PNPase)
Shepherd, D., Hathaway, Q., Pinti, M., Nichols, C., Durr, A., Sreekumar, S., Hughes, K. M., Stine, S. M., Martinez, I., & Hollander, J. (2017) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2017.06.012 · Cited by 80 · see citing works
“Though complete knockout of PNPase is embryonic lethal (93), a conditional animal knockout or cell culture knockout of PNPase should be examined in the future to observe how this impacts miRNA import into the mitochondria.”
Background
Mitochondrial activity in the regulation of stem cell self-renewal and differentiation
Khacho, M., & Slack, R. S. (2017) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2017.11.003 · Cited by 99 · see citing works
The Mitochondrial RNA Landscape of Saccharomyces cerevisiae
Turk, E. M., Das, V., Seibert, R., & Andrulis, E. D. (2013) · PLoS ONE · doi:10.1371/journal.pone.0078105 · Cited by 75 · see citing works
“PNPase is a phosphorolytic RNase PH-like exoribonuclease[17], while Rrp6p, Dss1p, and Dis3p are hydrolytic exoribonucleases of the RNase D[18], RNR (RNase II-like)[19,20], and RNase II/R family[21,22], respectively.”
BackgroundInfluential
A microRNA’s journey to the center of the mitochondria
Macgregor-Das, A. M., & Das, S. (2018) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00714.2017 · Cited by 76 · see citing works
ncRNAs: New Players in Mitochondrial Health and Disease?
Gušić, M., & Prokisch, H. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.00095 · Cited by 74 · see citing works
Organellar non-coding RNAs: emerging regulation mechanisms.
Dietrich, A., Wallet, C., Iqbal, R., Gualberto, J., & Lotfi, F. (2015) · Biochimie · doi:10.1016/j.biochi.2015.06.027 · Cited by 62 · see citing works
“As mentioned above, it has been reported that some tRNAs, the 5S rRNA, or the RNase MRP RNA can be imported into mammalian mitochondria [24,36].”
Background
Role of microRNA in metabolic shift during heart failure
Pinti, M. V., Hathaway, Q. A., & Hollander, J. M. (2016) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00341.2016 · Cited by 59 · see citing works
Regulating microRNA expression: at the heart of diabetes mellitus and the mitochondrion
Hathaway, Q. A., Pinti, M. V., Durr, A. J., Waris, S. A., Shepherd, D. L., & Hollander, J. M. (2017) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00520.2017 · Cited by 68 · see citing works
“(150, 151) demonstrated the importance Citric Acid Cycle”
Background
Leber Hereditary Optic Neuropathy: Exemplar of an mtDNA Disease
Wallace, D. C., & Lott, M. T. (2017) · Handbook of experimental pharmacology · doi:10.1007/164_2017_2 · Cited by 64 · see citing works
Defining the momiome: Promiscuous information transfer by mobile mitochondria and the mitochondrial genome
Singh, B., Modica-Napolitano, J. S., & Singh, K. K. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.05.004 · Cited by 49 · see citing works
“; More recent evidence, however, now demonstrates the trafficking of miRNAs and other biological molecules between the nucleus and mitochondria and the presence of miRNA processing machinery in mitochondria [54, 84, 85, 103, 104].”
Background
5′ modifications to CRISPR–Cas9 gRNA can change the dynamics and size of R-loops and inhibit DNA cleavage
Mullally, G., van Aelst, K., Naqvi, M. M., Diffin, F., Karvelis, T., Gasiunas, G., Šikšnys, V., & Szczelkun, M. (2020) · bioRxiv · doi:10.1093/nar/gkaa477 · Cited by 44 · see citing works
“To explore the effect of adding a structured RNA aptamer to SpCas9 gRNA, we utilised a 20 bp RP hairpin (Figure 5A) derived from a stem loop structure in the nuclear RNaseP RNP, that can direct import of RNA into mitochondria (25,32).”
Method
microRNAs in Mitochondria: An Unexplored Niche
Borralho, P. M., Rodrigues, C. M. P., & Steer, C. J. (2015) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-22380-3_3 · Cited by 48 · see citing works
Targeting nucleic acids into mitochondria: progress and prospects.
Niazi, A., Mileshina, D., Cosset, A., Val, R., Weber-Lotfi, F., & Dietrich, A. (2013) · Mitochondrion (Amsterdam. Print) · doi:10.1016/j.mito.2012.05.004 · Cited by 39 · see citing works
Fly Models of Human Diseases: Drosophila as a Model for Understanding Human Mitochondrial Mutations and Disease.
Sen, A., & Cox, R. T. (2017) · Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2016.07.001 · Cited by 38 · see citing works
Mitochondrial import, health and mtDNA copy number variability seen when using type II and type V CRISPR effectors
Antón, Z., Mullally, G., Ford, H. C., van der Kamp, M. W., Szczelkun, M., & Lane, J. (2020) · Journal of Cell Science · doi:10.1242/jcs.248468 · Cited by 34 · see citing works
“1B) (Holzmann et al., 2008; Puranam and Attardi, 2001; Wang et al., 2012).”
Mitochondrion-targeted RNA therapies as a potential treatment strategy for mitochondrial diseases
Chernega, T., Choi, J., Salmena, L., & Andreazza, A. C. (2022) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2022.10.012 · Cited by 38 · see citing works
“Cytosolic function: component of RNAse P, 50 tRNA maturation.153 Mitochondrial function: mitochondrial localization induces replicative cellular senescence.154 May play a role in mt-tRNA maturation as a part of mitochondrial RNAse P.155 Import mechanism: mediated by PNPase.130,156 Import determinants: 20-nt stem-loop,…”
BackgroundInfluential
Mitochondrial BMI1 maintains bioenergetic homeostasis in cells
Mustafi, S. B., Aznar, N., Dwivedi, S. K. D., Chakraborty, P. K., Basak, R., Mukherjee, P., Ghosh, P., & Bhattacharya, R. (2016) · The FASEB Journal · doi:10.1096/fj.201600321r · Cited by 31 · see citing works
“Recent evidences show that silencing ribonuclease PNPase leads to accumulation of RNA decay intermediates and increases the half-life of mitochondrial transcripts (54) thatmayormaynot involve suppressor of Var1, 3-like 1, a helicase partner (55-57).”
Background
Multidimensional crosstalk between RNA-binding proteins and noncoding RNAs in cancer biology.
Li, L., Miao, H., Chang, Y., Yao, H., Zhao, Y.-Y., Wu, F., & Song, X. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.03.007 · Cited by 31 · see citing works
Current Progress of Mitochondrial Genome Editing by CRISPR
Yin, T., Luo, J., Huang, D.-Q., & Li, H. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.883459 · Cited by 29 · see citing works
Nucleic acid import into mitochondria: New insights into the translocation pathways.
Weber-Lotfi, F., Koulintchenko, M., Ibrahim, N., Hammann, P., Mileshina, D., Konstantinov, Y., & Dietrich, A. (2015) · Biochimica et Biophysica Acta · doi:10.1016/j.bbamcr.2015.09.011 · Cited by 28 · see citing works
Crystal structure of dimeric human PNPase reveals why disease-linked mutants suffer from low RNA import and degradation activities
Golzarroshan, B., Lin, C.-L., Li, C.-L., Yang, W.-Z., Chu, L.-Y., Agrawal, S., & Yuan, H. S. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky642 · Cited by 25
“There, it is associated with importing structured RNA into the mitochondrial matrix, including RNase P RNA, MRP RNA, 5S rRNA and microRNAs (4,5,18).”
Background
Major 3'-5' Exoribonucleases in the Metabolism of Coding and Non-coding RNA.
Santos, R. D. D., Quendera, A. P., Boavida, S., Seixas, A. F., Arraiano, C., & Andrade, J. M. (2018) · Progress in Molecular Biology and Translational Science · doi:10.1016/bs.pmbts.2018.07.005 · Cited by 25 · see citing works
Trafficking of mitochondrial double-stranded RNA from mitochondria to the cytosol
Krieger, M. R., Abrahamian, M., He, K. L., Atamdede, S., Hakimjavadi, H., Momcilovic, M., Ostrow, D. G., Maggo, S. D. S., Tsang, Y. P., Gai, X., et al. (2024) · Life Science Alliance · doi:10.26508/lsa.202302396 · Cited by 19 · see citing works
“Mitochondrial PNPase has been shown to act as a gatekeeper to mediate the import of a subset of RNAs into mitochondria (Wang et al, 2010; Wang et al, 2012b; Vedrenne et al, 2012).”
Self-citation
Many Functions of Telomerase Components: Certainties, Doubts, and Inconsistencies
Udroiu, I., Marinaccio, J., & Sgura, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232315189 · Cited by 25 · see citing works
“PNPASE is directly involved in regulating RNA import and could work as an import channel [176,179].”
Background
tRNAs and proteins use the same import channel for translocation across the mitochondrial outer membrane of trypanosomes
Niemann, M., Harsman, A., Mani, J., Peikert, C. D., Oeljeklaus, S., Warscheid, B., Wagner, R., & Schneider, A. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1711430114 · Cited by 24 · see citing works
“Furthermore, some studies indicate that mammals import the 5S rRNA (15-17) and the RNA subunit of RNase P (18-20).”
Background
MicroRNAs as Factors in Bidirectional Crosstalk Between Mitochondria and the Nucleus During Cellular Senescence
Giordani, C., Silvestrini, A., Giuliani, A., Olivieri, F., & Rippo, M. R. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.734976 · Cited by 24 · see citing works
Mitochondrial MicroRNAs and Their Potential Role in Cell Function
Borralho, P. M., Rodrigues, C. M. P., & Steer, C. J. (2014) · Current Pathobiology Reports · doi:10.1007/s40139-014-0047-x · Cited by 24 · see citing works
Revisiting trends on mitochondrial mega-channels for the import of proteins and nucleic acids
Campo, M. L., Peixoto, P. M. V., & Martinez‐Caballero, S. (2016) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-016-9662-z · Cited by 20 · see citing works
Use of intracellular transport processes for targeted drug delivery into a specified cellular compartment
Rosenkranz, A. A., Ulasov, A. V., Slastnikova, T. A., Khramtsov, Y. V., & Sobolev, A. S. (2014) · Biochemistry (Moscow) · doi:10.1134/s0006297914090090 · Cited by 19 · see citing works
The mitochondrial long non-coding RNA lncMtloop regulates mitochondrial transcription and suppresses Alzheimer’s disease
Xiong, W., Xu, K., Sun, J. K.-L., Liu, S., Zhao, B., Shi, J., Herrup, K., Chow, H.-M., Lu, L., & Li, J. (2024) · The EMBO Journal · doi:10.1038/s44318-024-00270-7 · Cited by 17 · see citing works
“Our optimization process involved the fusion of lncMtDloop with the 3 ′ UTR of MRPS12 , facilitating its targeted localization to the mitochondrial surface — a technique supported by previous research (Chin et al, 2018; Wang et al, 2012b).”
Influential
Mitochondrial regulation in human pluripotent stem cells during reprogramming and β cell differentiation
Jasra, I. T., Cuesta‐Gomez, N., Verhoeff, K. K., Marfil‐Garza, B. A., Dadheech, N., & Shapiro, A. M. J. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1236472 · Cited by 17 · see citing works
“PnPase maintains mitochondrial homeostasis through facilitating the import of nucleus-encoded RNA required for mtDNA replication, transcription and translation (60) .”
Background
Identification of Genes Potentially Regulated by Human Polynucleotide Phosphorylase (hPNPaseold-35) Using Melanoma as a Model
Sokhi, U. K., Bacolod, M., Dasgupta, S., Emdad, L., Das, S. K., Dumur, C., Miles, M., Sarkar, D., & Fisher, P. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076284 · Cited by 17 · see citing works
“There are also studies providing evidence that hPNPase is a regulator of mitochondrial RNA import and plays a role in mtRNA processing [23-27].”
Background
Mitochondria-Targeted RNA Import
Geng, W., Shimada, E., Nili, M., Koehler, C., & Teitell, M. (2015) · Methods in molecular biology · doi:10.1007/978-1-4939-2257-4_11 · Cited by 17
“1 Introduction Mitochondria import a range of nucleus-encoded RNAs, with different species having different substrate specificities [1].”
BackgroundSelf-citation
Human polynucleotide phosphorylase (hPNPaseold-35): should I eat you or not--that is the question?
Sokhi, U. K., Das, S. K., Dasgupta, S., Emdad, L., Shiang, R., DeSalle, R., Sarkar, D., & Fisher, P. (2013) · Advances in Cancer Research · doi:10.1016/b978-0-12-407190-2.00005-8 · Cited by 16 · see citing works
“The level of hPNPaseold-35 knockdown seems to play a critical role in deciding the observable changes in mitochondrial physiology and function (Chen et al., 2006; Wang et al., 2012).”
Background
Spatial analysis of mitochondrial gene expression reveals dynamic translation hubs and remodeling in stress
Begeman, A., Smolka, J. A., Shami, A., Waingankar, T., & Lewis, S. C. (2025) · Science Advances · doi:10.1126/sciadv.ads6830 · Cited by 14 · see citing works
“Previous work has shown that pathogenic variants that disrupt mitochondrial protein synthesis converge on activation of a complex ISR, characterized in part by shutoff of mitoribosome translation and accumulation of aberrant double-stranded mtRNA ( 25 , 26 , 34 , 35 ).”
Activity and Function in Human Cells of the Evolutionary Conserved Exonuclease Polynucleotide Phosphorylase
Falchi, F. A., Pizzoccheri, R., & Briani, F. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031652 · Cited by 14 · see citing works
“Accordingly, PNPT1 expression in the absence of IFN-β stimulation has been found in different types of cells [14,18,19].”
Background
A Novel Pathway of Functional microRNA Uptake and Mitochondria Delivery
Liu, J., Li, W.-L., Li, J., Song, E., Liang, H.-W., Rong, W., Jiang, X., Xu, N., Wang, W., Qu, S., et al. (2022) · bioRxiv · doi:10.1002/advs.202300452 · Cited by 13
“As a RNA-binding protein, PNPT1 plays multiple role in RNA transport and degradation (Wang et al., 2012).”
Background
RNase III-Independent Autogenous Regulation of Escherichia coli Polynucleotide Phosphorylase via Translational Repression
Carzaniga, T., Dehò, G., & Briani, F. (2015) · Journal of Bacteriology · doi:10.1128/jb.00105-15 · Cited by 13
Novel drug-delivery approaches to the blood-brain barrier
Wang, X., Yu, X.-W., Vaughan, W., Liu, M., & Guan, Y. (2015) · Neuroscience Bulletin · doi:10.1007/s12264-014-1498-0 · Cited by 12 · see citing works
Highly Multiplexed RNA Aptamer Selection using a Microplate-based Microcolumn Device
Reinholt, S. J., Ozer, A., Lis, J., & Craighead, H. (2016) · Scientific Reports · doi:10.1038/srep29771 · Cited by 11 · see citing works
Import of desired nucleic acid sequences using addressing motif of mitochondrial ribosomal 5S-rRNA for fluorescent in vivo hybridization of mitochondrial DNA and RNA
Zelenka, J., Alán, L., Jabůrek, M., & Ježek, P. (2014) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-014-9543-2 · Cited by 11 · see citing works
Analysis of global changes in gene expression induced by human polynucleotide phosphorylase (hPNPaseold-35)
Sokhi, U. K., Bacolod, M., Emdad, L., Das, S. K., Dumur, C., Miles, M., Sarkar, D., & Fisher, P. (2014) · Journal of Cellular Physiology · doi:10.1002/jcp.24645 · Cited by 10
Mitochondrial RNA in Inflammation
Chen, J., You, C., Xie, H.-B., & Zhu, Q.-X. (2025) · International Journal on Biological Sciences · doi:10.7150/ijbs.119841 · Cited by 9
How RNases Shape Mitochondrial Transcriptomes
Cartalas, J., Coudray, L., & Gobert, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23116141 · Cited by 8 · see citing works
Functions of Conserved Domains of Human Polynucleotide Phosphorylase on RNA Oxidation
Malla, S., & Li, Z.-W. (2019) · Insights of Biomedical Research · doi:10.36959/584/448 · Cited by 8
“Some reported that hPNPase is a mitochondrial intermembrane protein whereas other claimed that it is predominantly localized in the mitochondrial matrix [20,21,27].”
Background
Mitochondrion-to-nucleus communication mediated by RNA export: a survey of potential mechanisms and players across eukaryotes
Muneretto, G., Plazzi, F., & Passamonti, M. (2024) · Biology Letters · doi:10.1098/rsbl.2024.0147 · Cited by 7
“In eukaryotes, it appears to be highly conserved, but it is absent in some fungi and in T. brucei [47].”
Background
Engineering Genetic Systems for Treating Mitochondrial Diseases
Jang, Y., Ahn, S. R., Shim, J.-Y., & Lim, K. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13060810 · Cited by 9 · see citing works
“Abbreviation ATP adenosine triphosphate AAV adeno-associated virus AD Alzheimer’s disease adPEO autosomal dominant PEO AHS Alpers–Huttenlocher syndrome ANS ataxia neuropathy spectrum arPEO autosomal recessive PEO ASO antisense RNA oligonucleotide cap capsid COX cytochrome oxidase CPEO chronic PEO CPEO chronic progress…”
BackgroundInfluential
Recent advances in delivering RNA-based therapeutics to mitochondria
Yamada, Y., Ishizuka, S., Arai, M., Maruyama, M., & Harashima, H. (2022) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2022.2070427 · Cited by 7 · see citing works
“encoded by the PNPT1 gene, which is a native RNA transport enzyme that is located in the mitochondrial intermembrane space [61].”
Background
Delivery Cas9 into mitochondria
Orishchenko, K., Sofronova, J. K., Chupakhin, E. G., Lunev, E., & Mazunin, I. (2016) · Genes & Cells · doi:10.23868/gc120599 · Cited by 5 · see citing works
Mitochondrial Genetic Manipulation
Mileshina, D., Niazi, A., Weber-Lotfi, F., Gualberto, J., & Dietrich, A. (2015) · Springer eBooks · doi:10.1007/978-1-4939-2389-2_13 · Cited by 5 · see citing works
Protein coding mitochondrial-targeted RNAs rescue mitochondrial disease in vivo
Markantone, D. M., Towheed, A., Crain, A. T., Collins, J. M., Celotto, A. M., & Palladino, M. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.06.009 · Cited by 4 · see citing works
Intercompartment RNA Trafficking in Mitochondrial Function and Communication
Weber-Lotfi, F., & Dietrich, A. (2018) · Nucleic acids and molecular biology · doi:10.1007/978-3-319-78190-7_4 · Cited by 4 · see citing works
Mitochondrial and Reactive Oxygen Species Signaling Coordinate Stem Cell Fate Decisions and Life Long Maintenance
Khacho, M., & Slack, R. S. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7228 · Cited by 53 · see citing works
Feedforward miR-181d degradation modulates population variance of methyl-guanine methyl transferase and temozolomide resistance
Singh, G., Singh, S., Mohapatra, I., Kim, S., Sharma, M., Akers, J., Nguyen, T., Wong, E. T., Moreno, M. M., Kokkoli, E., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116516 · Cited by 3 · see citing works
“41,42 In this study, we demonstrate that TMZ treatment activates the ATR kinase to initiate a feed-forward PNPT1-miR-181d loop that expedites PNPT1-dependent degradation of miR-181d.”
Non-coding RNA and reprogrammed mitochondrial metabolism in genitourinary cancer
Thirunavukkarasu, S., Banerjee, S., Tantray, I., & Ojha, R. (2024) · Frontiers in Genetics · doi:10.3389/fgene.2024.1364389 · Cited by 2 · see citing works
“…mitochondrial importation (Liu et al., 2019; Liu et al., 2020). mtcciND1 and mtcciND5 interact with translocase of the outer membrane of mitochondria 40 (TOM40) and polynucleotide phosphorylase (PNPASE), to act as molecular chaperones (Gabriel et al., 2003; Wang et al., 2010; Wang et al., 2012).”
Background
A new member in the Argonaute crew: the mt-miRNAs
Pozzi, A., & Dowling, D. (2020) · bioRxiv · doi:10.1101/2020.02.13.948554 · Cited by 3
“Indeed, proteins like the PNPase have been demonstrated to be involved in RNA translocation through the mitochondrial membrane (Wang et al. 2012).”
Background
Mitochondrial Biology and Medicine
Wallace, D. C., Lott, M. T., & Procaccio, V. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-812537-3.00010-x · Cited by 7 · see citing works
Import of Fluorescent RNA into Mitochondria of Living Cells.
Zelenka, J., & Ježek, P. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-3040-1_13 · Cited by 3
Mitochondrial cytopathies: Their causes and correction pathways
Teplova, V., Deryabina, Y., & Isakova, E. (2017) · Biochemistry (Moscow) Supplement Series A Membrane and Cell Biology · doi:10.1134/s1990747817020088 · Cited by 2 · see citing works
“Nucleic acids can be delivered into mitochondria through a Voltage Dependent Anion Channel (VDAC) or via TIM/TOM transporters [58, 59].”
Mitochondrial genome editing tools: prospects in animal breeding
Xu, Y., Chen, M., Yang, S., Guo, Y., Dai, Y., Chen, Y., Zhong, H., Ma, T., Zha, D., He, Y., et al. (2026) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2026.02.018 · Cited by 1 · see citing works
A spatial atlas of mitochondrial gene expression reveals dynamic translation hubs and remodeling in stress
Begeman, A., Smolka, J. A., Shami, A., Waingankar, T., & Lewis, S. C. (2024) · bioRxiv · doi:10.1101/2024.08.05.604215 · Cited by 1
“…has shown that pathogenic variants that disrupt mitochondrial protein synthesis converge on activation of a complex integrated stress response (ISR), characterized in part by shutoff of mitoribosome translation and accumulation of aberrant double-stranded mitochondrial RNA ( 22 , 23 , 31 , 32 ).”
Background
Targeting Therapeutic Nucleic Acids into Mitochondria: A Long Challenge
Weber-Lotfi, F., & Dietrich, A. (2018) · doi:10.1007/978-3-319-73344-9_25 · Cited by 1
Phenotypic characterization of PNPase knockdown in C. elegans
Lambert, L. A. (2015) · VCU Scholars Compass (Virginia Commonwealth University) · doi:10.25772/xbhy-2111 · Cited by 1 · see citing works
“…degrading c-myc mRNA (Sarkar et al., 2003; Sarkar et. al., 2005), miR-221, miR222, and miR-106b (Das et. al., 2010), and regulating translocation of small RNAs into the mitochondria, such as MRP (mitochondrial RNA processing), 5S rRNA, and RNase P (Wang et al., 2010; Wang et al., 2012).”
Background
Spatiotemporal Control of microRNA –Target Interactions
Le, L. T. T. (2026) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.70053
“Consistent with this model, mouse skin cells contain ~1.4–1.7 × 10 5 AGO molecules (Wang, Shimada, et al. 2012; Wang, Zhang, et al. 2012), and increased AGO levels enhance RNAi FIGURE 6 | Kinetic cycle of AGO turnover in miRNA silencing.”
Influential
Modulating populational variance of methyl-guanine methyl transferase expression through miR-181d degradation: a novel mechanism of temozolomide resistancePreprint
Singh, G., Singh, S., Mohapatra, I., Kim, S., Sharma, M., Akers, J., Nguyen, T., Wong, E. T., Moreno, M. M., Kokkoli, E., et al. (2025) · bioRxiv · doi:10.1101/2025.04.22.650094
“Separate-of-function PNPT1 mutations have been reported for these distinct functions (39, 40).”
A novel polyribonucleotide nucleotidyltransferase 1 (PNPT1) gene variant potentially associated with combined oxidative phosphorylation deficiency 13: case report and literature review
Li, Y.-Y., Gao, Y., Zhong, X., & Chen, G.-F. (2025) · Translational Pediatrics · doi:10.21037/tp-24-419
“Furthermore, disruptions in RNA processing can lead to the accumulation of double-stranded mt-RNA in mitochondria, which may leak into the cytoplasm, activating antiviral signaling pathways and triggering a type I interferon response (6,25).”
Mitochondrial transport of catalytic RNAs and targeting of the organellar transcriptome in human cells
Głodowicz, P., Kuczyński, K., Val, R., Dietrich, A., & Rolle, K. (2023) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjad051
“Indeed, in many organisms, mitochondria are able to take up various types of RNAs ( Salinas et al., 2008 ; Sieber et al., 2011 ; Wang et al., 2012a ; Warren and Sloan, 2020 ) .”
Influential
Role of the PNPase enzyme in the transport of mtRNA in lymphatic cancer: Bibliographic review
Piqueras, M. L., & González, I. V. (2021) · Nereis. Interdisciplinary Ibero-American Journal of Methods, Modelling and Simulation. · doi:10.46583/nereis_2021.13.786
“The protein is located in the intermembrane space (IMS), although it has also been detected in the mitochondrial matrix [15-17].”
Background
Suppression of PNPase Alleviates Gestational Diabetes Mellitus-cardiovascular Injury through Up-regulating MicroRNA-26a and Down-regulating PTEN
Liu, L., Wu, H., & Cheng, X. (2021) · doi:10.21203/rs.3.rs-720762/v1
Variability in mitochondrial import, mitochondrial health and mtDNA copy number using Type II and Type V CRISPR effectors
Antón, Z., Mullally, G., Ford, H. C., van der Kamp, M. W., Szczelkun, M., & Lane, J. (2020) · bioRxiv · doi:10.1101/2020.03.10.985606
“In mammalian cells, mitochondrial import of 5S ribosomal RNA (rRNA), mitochondrial RNase P RNA (MRP), and RNase P RNA (RP) occurs by unknown mechanisms, although evidence implicates factors including Rhodanese (Rhod) in the case of the 5S rRNA [45-47], and possibly PNPase during 5S, MRP and RP RNA import [48-50] (Figu…”
Background
RNA import into mitochondria and its use in gene therapy
Lakunina, V., Baleva, M. V., Levitskii, S., Chicherin, I., Krasheninnikov, I. A., Samoylova, E., & Kamenski, P. (2015) · Moscow University Biological Sciences Bulletin · doi:10.3103/s0096392515030062
Cardiac and Mitochondrial Dysfunction during Diabetes Mellitus: Examination of Mitochondrial Import Mechanisms
Shepherd, D. (2017) · doi:10.33915/etd.6629
A Study of Magnetic Reconnection: From 2D Energy Release to 3D Spreading and Localization
Shepherd, L. (2014) · doi:10.33915/etd.204
RNA Technologies for Mitochondrial Genetics
Dietrich, A., Rolle, K., Gabryelska, M. M., Wyszko, E., Val, R., Szymanski, M., Valentin, C., Cosset, A., & Barciszewski, J. (2012) · RNA technologies · doi:10.1007/978-3-642-27426-8_13

Authors: Wang, G., Shimada, E., Koehler, C. M., & Teitell, M. A.
Affiliations: University of California, Los Angeles (US)
California NanoSystems Institute (US)
Corresponding author: Koehler, Carla M.
Teitell, Michael A.
ORCID: Wang, Geng
Koehler, Carla M.
Teitell, Michael A.
Venue: Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Publisher: Elsevier BV
Published: 2012-09
Volume: 1819
Issue: 9-10
Pages: 998-1007
ISSN: 1874-9399 (ISSN-L)
DOI: 10.1016/j.bbagrm.2011.10.001
PMC: PMC3267854
OpenAlex: W1989149623
Cited by: 84
References: 122
Citations by year: 2026: 3 · 2025: 4 · 2024: 5 · 2023: 4 · 2022: 7 · 2021: 7 · 2020: 3 · 2019: 3 · 2018: 6 · 2017: 12 · 2016: 6 · 2015: 11 · 2014: 4 · 2013: 3 · 2012: 6
FWCI: 0.38
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: NIH
Muscular Dystrophy Association
American Heart Association
California Institute of Regenerative Medicine
UCLA Molecular Biology Institute
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
Keywords: polynucleotide phosphorylase, mitochondrial biogenesis, intermembrane space, mitochondrial gene expression
MeSH terms: Animals, Cell Nucleus, Exoribonucleases, Humans, Mitochondria, Oxidative Phosphorylation, Plants, RNA, Transfer, Saccharomyces cerevisiae, RNA, Nuclear, Mitochondrial Proteins, RNA Transport

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PNPASE and RNA trafficking into mitochondria

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