ArticlePloS one2018
PNPase knockout results in mtDNA loss and an altered metabolic gene expression program.
Article in PloS one, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 24 citations in OpenAlex.
- The impact of macrophage metabolism on idiopathic pulmonary fibrosis development and treatment prospectives.Frontiers in immunology · 2026Review
- Human polynucleotide phosphorylase in mitochondrial RNA metabolism.Bioscience reports · 2025Review
- Structural insights into human PNPase in health and disease.Nucleic acids research · 2025Article
- Mechanisms underlining R-loop biology and implications for human disease.Frontiers in cell and developmental biology · 2025Review
- Pathological PNPase variants with altered RNA binding and degradation activity affect the phenotype of bacterial and human cell models.NAR molecular medicine · 2025Article
- Mitochondria facilitate neuronal differentiation by metabolising nuclear-encoded RNA.Cell communication and signaling : CCS · 2024Article
- Trafficking of mitochondrial double-stranded RNA from mitochondria to the cytosol.Life science alliance · 2024Article
- Mitochondrial sequencing identifies long noncoding RNA features that promote binding to PNPase.American journal of physiology. Cell physiology · 2024Article
- Mitochondrial DNA Instability Supersedes Parkin Mutations in Driving Mitochondrial Proteomic Alterations and Functional Deficits in Polg Mutator Mice.International journal of molecular sciences · 2024Article
- Human PNPase causes RNA stabilization and accumulation of R-loops in the Escherichia coli model system.Scientific reports · 2023Article
- SP1 and NFY Regulate the Expression ofInternational journal of molecular sciences · 2022Article
- How RNases Shape Mitochondrial Transcriptomes.International journal of molecular sciences · 2022Review
- Activity and Function in Human Cells of the Evolutionary Conserved Exonuclease Polynucleotide Phosphorylase.International journal of molecular sciences · 2022Review
- Loss ofeLife · 2021Article
- Polynucleotide phosphorylase: Not merely an RNase but a pivotal post-transcriptional regulator.PLoS genetics · 2018Review
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 1 country.
Funding
Abstract
Polynucleotide phosphorylase (PNPase) is an essential mitochondria-localized exoribonuclease implicated in multiple biological processes and human disorders. To reveal role(s) for PNPase in mitochondria, we established PNPase knockout (PKO) systems by first shifting culture conditions to enable cell growth with defective respiration. Interestingly, PKO established in mouse embryonic fibroblasts (MEFs) resulted in the loss of mitochondrial DNA (mtDNA). The transcriptional profile of PKO cells was similar to rho0 mtDNA deleted cells, with perturbations in cholesterol (FDR = 6.35 x 10-13), lipid (FDR = 3.21 x 10-11), and secondary alcohol (FDR = 1.04x10-12) metabolic pathway gene expression compared to wild type parental (TM6) MEFs. Transcriptome analysis indicates processes related to axonogenesis (FDR = 4.49 x 10-3), axon development (FDR = 4.74 x 10-3), and axonal guidance (FDR = 4.74 x 10-3) were overrepresented in PKO cells, consistent with previous studies detailing causative PNPase mutations in delayed myelination, hearing loss, encephalomyopathy, and chorioretinal defects in humans. Overrepresentation analysis revealed alterations in metabolic pathways in both PKO and rho0 cells. Therefore, we assessed the correlation of genes implicated in cell cycle progression and total metabolism and observed a strong positive correlation between PKO cells and rho0 MEFs compared to TM6 MEFs. We quantified the normalized biomass accumulation rate of PKO clones at 1.7% (SD ± 2.0%) and 2.4% (SD ± 1.6%) per hour, which was lower than TM6 cells at 3.3% (SD ± 3.5%) per hour. Furthermore, PKO in mouse inner ear hair cells caused progressive hearing loss that parallels human familial hearing loss previously linked to mutations in PNPase. Combined, our study reports that knockout of a mitochondrial nuclease results in mtDNA loss and suggests that mtDNA maintenance could provide a unifying connection for the large number of biological activities reported for PNPase.
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