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 80 publications

(66 citation statements)

References 115 publications

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“…This dynamic led to a decrease in cellular ATP content and bioenergetics [50]. Polynucleotide Phosphorylase (PNPase), situated in the inner mitochondrial membrane and extending into the intermembrane space, is known to facilitate the transport of ribosomal RNA (rRNA) and transfer RNA (tRNA) based on their hairpin-loop structure [3,92,93]. PNPase also functions to edit and degrade RNA, as well as plays a role in controlling cellular senescence and cell cycle [59,76,77,80].…”

Section: Introductionmentioning

confidence: 99%

Exploring the mitochondrial microRNA import pathway through Polynucleotide Phosphorylase (PNPase)

Shepherd

Hathaway

Pinti

et al. 2017

Journal of Molecular and Cellular Cardiology

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Cardiovascular disease is the primary cause of mortality for individuals with type 2 diabetes mellitus. During the diabetic condition, cardiovascular dysfunction can be partially attributed to molecular changes in the tissue, including alterations in microRNA (miRNA) interactions. MiRNAs have been reported in the mitochondrion and their presence may influence cellular bioenergetics, creating decrements in functional capacity. In this study, we examined the roles of Argonaute 2 (Ago2), a protein associated with cytosolic and mitochondrial miRNAs, and Polynucleotide Phosphorylase (PNPase), a protein found in the inner membrane space of the mitochondrion, to determine their role in mitochondrial miRNA import. In cardiac tissue from human and mouse models of type 2 diabetes mellitus, Ago2 protein levels were unchanged while PNPase protein expression levels were increased; also, there was an increase in the association between both proteins in the diabetic state. MiRNA-378 was found to be significantly increased in db/db mice, leading to decrements in ATP6 levels and ATP synthase activity, which was also exhibited when overexpressing PNPase in HL-1 cardiomyocytes and in HL-1 cells with stable miRNA-378 overexpression (HL-1-378). To assess potential therapeutic interventions, flow cytometry evaluated the capacity for targeting miRNA-378 species in mitochondria through antimiR treatment, revealing miRNA-378 level-dependent inhibition. Our study establishes PNPase as a contributor to mitochondrial miRNA import through the transport of miRNA-378, which may regulate bioenergetics during type 2 diabetes mellitus. Further, our data provide evidence that manipulation of PNPase levels may enhance the delivery of antimiR therapeutics to mitochondria in physiological and pathological conditions.

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Section: Introductionmentioning

confidence: 99%

Exploring the mitochondrial microRNA import pathway through Polynucleotide Phosphorylase (PNPase)

Shepherd

Hathaway

Pinti

et al. 2017

Journal of Molecular and Cellular Cardiology

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“…The ribosomal protein L18 serves as a conduit or chaperone to facilitate the association of the imported 5S ribosomal RNA with mitochondrial ribosomes. And the mammalian polynucleotide phosphorylase (PNPASE) enzyme localizes to the mitochondrial intermembrane space (18)(19)(20) where it may function as an RNA receptor to augment translocation of RNAs into the mitochondrial matrix (6,21).…”

mentioning

confidence: 99%

Correcting human mitochondrial mutations with targeted RNA import

Wang¹,

Shimada²,

Zhang³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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120

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Mutations in the human mitochondrial genome are implicated in neuromuscular diseases, metabolic defects, and aging. An efficient and simple mechanism for neutralizing deleterious mitochondrial DNA (mtDNA) alterations has unfortunately remained elusive. Here, we report that a 20-ribonucleotide stem-loop sequence from the H1 RNA, the RNA component of the human RNase P enzyme, appended to a nonimported RNA directs the import of the resultant RNA fusion transcript into human mitochondria. The methodology is effective for both noncoding RNAs, such as tRNAs, and mRNAs. The RNA import component, polynucleotide phosphorylase (PNPASE), facilitates transfer of this hybrid RNA into the mitochondrial matrix. In addition, nucleus-encoded mRNAs for mitochondrial proteins, such as the mRNA of human mitochondrial ribosomal protein S12 (MRPS12), contain regulatory sequences in their 3′-untranslated region (UTR) that confers localization to the mitochondrial outer membrane, which is postulated to aid in protein translocation after translation. We show that for some mitochondrial-encoded transcripts, such as COX2, a 3′-UTR localization sequence is not required for mRNA import, whereas for corrective mitochondrial-encoded tRNAs, appending the 3′-UTR localization sequence was essential for efficient fusion-transcript translocation into mitochondria. In vivo, functional defects in mitochondrial RNA (mtRNA) translation and cell respiration were reversed in two human disease lines. Thus, this study indicates that a wide range of RNAs can be targeted to mitochondria by appending a targeting sequence that interacts with PNPASE, with or without a mitochondrial localization sequence, providing an exciting, general approach for overcoming mitochondrial genetic disorders.

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“…Nevertheless, mitochondrial import of these RNAs was further reported and seems to involve polynucleotide phosphorylase (PNPase; Wang et al 2010). PNPase, a 3'-5' exoribonuclease localized in the mitochondrial intermembrane space, would thus have another role in regulating the import of selected nucleus-encoded RNAs, including the RNase P/RNase MRP RNAs and the 5S rRNA (Wang et al 2010(Wang et al , 2012a. It was proposed that PNPase recognizes a stem-loop structure in the RNAs that it helps to import.…”

Section: Pnpase-facilitated Rna Targetingmentioning

confidence: 98%