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Mitochondrial RNA degradation is increased in AML and controls differentiation, stem cell function and sensitivity to immune-mediated killing [RNA-seq]

ABSTRACT: Eukaryotic cells have two separate genomes that are replicated independently; nuclear DNA organized in chromosomes and circular DNA within mitochondria. Mitochondrial DNA is transcribed bi-directionally to generate mitochondrial RNA (mtRNA). As a by-product of the bi-directional transcription, dsRNA is also generated. By gene expression analysis and functional studies, we demonstrated that mtRNA transcription and degradation were increased in AML (Acute Myeloid Leukemia) cells and stem cells resulting in higher rates of mtRNA turnover. We discovered that the mitochondrial degradosome, SUV3 and PNPase, was upregulated in AML cells and stem cells and functionally important for the degradation of mtRNA and mitochondrial dsRNA in AML. Depleting SUV3 or PNPase impaired mtRNA degradation and promoted the accumulation of dsRNA. dsRNA that accumulated after depleting SUV3 or PNPase, stimulated IFN-I signaling that induced AML differentiation, decreased stem cell function and increased sensitivity of AML cells to immune-mediating killing. Thus, this work highlights new mitochondrial biology in AML and a novel mechanism by which the turnover of mtRNA regulates AML differentiation and stem cell function

ORGANISM(S): Homo sapiens

PROVIDER: GSE297113 | GEO | 2026/02/26

REPOSITORIES: GEO

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Mitochondrial RNA degradation is increased in AML and controls differentiation, stem cell function and sensitivity to immune-mediated killing [NS_Immunology_v2_C2328]

Project description:Eukaryotic cells have two separate genomes that are replicated independently; nuclear DNA organized in chromosomes and circular DNA within mitochondria. Mitochondrial DNA is transcribed bi-directionally to generate mitochondrial RNA (mtRNA). As a by-product of the bi-directional transcription, dsRNA is also generated. By gene expression analysis and functional studies, we demonstrated that mtRNA transcription and degradation were increased in AML (Acute Myeloid Leukemia) cells and stem cells resulting in higher rates of mtRNA turnover. We discovered that the mitochondrial degradosome, SUV3 and PNPase, was upregulated in AML cells and stem cells and functionally important for the degradation of mtRNA and mitochondrial dsRNA in AML. Depleting SUV3 or PNPase impaired mtRNA degradation and promoted the accumulation of dsRNA. dsRNA that accumulated after depleting SUV3 or PNPase, stimulated IFN-I signaling that induced AML differentiation, decreased stem cell function and increased sensitivity of AML cells to immune-mediating killing. Thus, this work highlights new mitochondrial biology in AML and a novel mechanism by which the turnover of mtRNA regulates AML differentiation and stem cell function

2026-02-26 | GSE297053 | GEO

Mitochondrial dsRNA triggers antiviral signalling in humans

Project description:Mitochondria are descendants of endosymbiotic bacteria and retain essential prokaryotic features such as a compact circular genome. Consequently, in mammals, mitochondrial DNA is subjected to bidirectional transcription that generates overlapping transcripts capable of forming long double-stranded RNA structures. However, to our knowledge, mitochondrial double-stranded RNA has not been previously characterized in vivo. Here, we describe the presence of a highly unstable native mitochondrial double-stranded RNA species at single cell level and identify keyroles for the degradosome components, mitochondrial dsRNA helicase SUV3 and polynucleotide phosphorylase PNPase in restricting the levels of mitochondrial double-stranded RNA. Loss of either enzyme results in massive accumulation of mitochondrial double-stranded RNA that escapes into the cytoplasm in a PNPase-dependent manner. This process engages an MDA5-driven antiviral signalling pathway that triggers a type I interferon response. Consistent with these data, patients carrying hypomorphic mutations in the gene PNPT1, which encodes PNPase, display mitochondrial double-stranded RNA accumulation coupled with upregulation of interferon-stimulated genes and other markers of immune activation. The localization of PNPase to the mitochondrial inter-membrane space and matrix suggests that it has a dual role in preventing the formation and release of mitochondrial double-stranded RNA into the cytoplasm. This in turn prevents the activation of potent innate immune defence mechanisms evolved to protect vertebrates against microbial and viral attack.

2018-05-03 | GSE94957 | GEO

Defects of mitochondrial RNA turnover lead to the accumulation of double-stranded RNA in vivo

Project description:The RNA helicase SUV3 and the polynucleotide phosphorylase PNPase are involved in the degradation of mitochondrial mRNAs but their roles in vivo are not fully understood. Additionally, upstream processes, such as transcript maturation, have been linked to some of these factors, suggesting either dual roles or tightly interconnected mechanisms of mitochondrial RNA metabolism. To get a better understanding of the turn-over of mitochondrial RNAs in vivo, we manipulated the mitochondrial mRNA degrading complex in Drosophila melanogaster models and studied the molecular consequences. Additionally, we investigated if and how these factors interact with the mitochondrial poly(A) polymerase, MTPAP, as well as with the mitochondrial mRNA stabilising factor, LRPPRC. Our results demonstrate a tight interdependency of mitochondrial mRNA stability, polyadenylation and the removal of antisense RNA. Furthermore, disruption of degradation, as well as polyadenylation, leads to the accumulation of double-stranded RNAs, and their escape out into the cytoplasm is associated with an altered immune-response in flies. Together our results suggest a highly organised and inter-dependable regulation of mitochondrial RNA metabolism with far reaching consequences on cellular physiology.

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Identification of proteins associated with the human mitochondrial degradosome

Project description:The human mitochondrial degradosome is a complex of the ribonuclease PNPase (Q8TCS8, encoded by PNPT1 gene) and RNA helicase SUV3 (Q8IYB8, encoded by SUPV3L1 gene). The aim of the project was to identify proteins which co-purify with both subunits of the degradosome. To this end we used human 293 cells stably expressing hSuv3 or PNPase with a C-terminal TAP tag or TAP tag fused to a mitochondria targeting sequence (control bait) (cell lines are described in details in (PMID: 19864255). Mitochondria were isolated from the cells, lysed and the protein extracts were subjected to affinity chromatography. Co-purified proteins were identified by mass spectrometry and their amounts were quantified by a label-free approach (MaxQuant). These experiments are part of the project “Dedicated surveillance mechanism controls G-quadruplex forming non-coding RNAs in human mitochondria”.

2018-07-06 | PXD009826 | Pride

Analysis of global changes in gene expression induced by human polynucleotide phosphorylase (hPNPaseold-35)

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Gene Expression Signature of Human Polynucleotide Phosphorylase (hPNPaseold-35) in Melanoma

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Mitochondrial double stranded RNA Dependent Lipid Reprogramming in Non-Small Cell Lung Cancer

Project description:Transcription of the mitochondrial genome results in the generation of double stranded RNA. Escape of mitochondrial double stranded RNA (mtdsRNA) into the cytosol is deleterious and functions as a class of damage associated molecular pathogens (DAMPs) that elicits activation of an anti-viral response in cells. To mitigate the harmful consequences of excess cytosolic mtdsRNA, mammalian cells rely on the mitochondria localized exonuclease polynucleotide phosphorylase (PNPase) to degrade excess mtdsRNA. While the regulation of mtdsRNA by PNPase has been studied in the non-cancerous cells and tissue(s), less is known about the role PNPase plays in cancer cells nor the cellular consequences that PNPase inhibition and the dysregulation of mtdsRNA degradation has on tumor cells. Here, we demonstrate that PNPase inactivation in a Kras-driven, Lkb1 mutant (KL) genetically engineered mouse model (GEMM) of lung cancer resulted in a significant extension in overall survival of mice and reduced tumor cell proliferation. PNPase loss activated a robust interferon-stimulated viral mimicry response in lung tumors that triggered reprograming of lipid metabolism and upregulation of lipid droplet biogenesis in tumor cells. Tumors that escaped PNPase loss transformed into fatty lesions characterized by a substantial accumulation of lipid droplets enriched for polyunsaturated fatty acids (PUFAs). Importantly, PNPase null KL tumors were highly sensitive to ferroptosis, which resulted in the ablation and near complete clearance of tumors from the lung of mice. Similarly, targeted pharmacological inhibition of PNPase sensitized therapy resistant human lung and pancreatic tumor cells to ferroptosis. These findings demonstrate that PNPase represents a new class of molecular target and identified that viral mimicry and lipid droplet biogenesis may be readily exploited for the treatment of therapy resistant lung and pancreatic tumors.

2025-12-03 | GSE311868 | GEO

Exoribonucleases coordinate degradation and expression of mRNAs in Escherichia coli at the stationary phase [transcriptome]

Project description:Exoribonucleases are crucial for RNA degradation in Escherichia coli but the roles of RNase R and PNPase and their potential overlap in stationary phase are not well characterized. Here, we used a genome-wide approach to determine how RNase R and PNPase affect the mRNA half-lives compared to wild type (stabilome) in the stationary phase. The stabilome is an original dynamic transcriptome-based analysis to measure the rates of mRNA degradation at the genome scale. We have combined the analysis of stabilome with the steady state concentrations of mRNAs (transcriptome) to provide an integrated overview of the in vivo activity of these exoribonucleases at the genome-scale. The stabilome demonstrated that the mRNAs are very stable in the stationary phase and that the deletion of RNase R or PNPase caused only a limited mRNA stabilization. Intriguingly the absence of PNPase provoked also the destabilization of many mRNAs. These changes in mRNA half-lives in the PNPase deletion strain were associated with a massive reorganization of mRNA levels and also variation in several ncRNA concentrations. Finally, the in vivo activity of the degradation machinery was found frequently saturated by mRNAs in the PNPase mutant unlike in the RNase R mutant, suggesting that the degradation activity is limited by the deletion of PNPase but not by the deletion of RNase R. This work allowed the roles of RNase R and PNPase in coordinating E. coli RNA metabolism to be discussed and PNPase to be identified as a central player of the degradation machinery in stationary phase.

2018-12-10 | GSE116577 | GEO

Exoribonucleases coordinate degradation and expression of mRNAs in Escherichia coli at the stationary phase [stabilome]

2018-12-10 | GSE116576 | GEO

Gene Expression Signature of Human Polynucleotide Phosphorylase (hPNPaseold-35) in Melanoma

Project description:Human Polynucleotide Phosphorylase (hPNPaseold-35) is an evolutionarily conserved 3’→5’ exoribonuclease implicated in the regulation of numerous physiological processes like maintenance of mitochondrial homeostasis, mtRNA import and aging-associated inflammation. From an RNase perspective, little is known about the RNA or miRNA species it targets for degradation or whose expression it regulates; except for c-myc and miR-221. To further elucidate the functional implications of hPNPaseold-35 in cellular physiology, we knocked-down and overexpressed hPNPaseold-35 in melanoma cells and performed gene expression analyses to identify differentially expressed transcripts. Biological triplicates were run on microarrays.

2013-07-30 | E-GEOD-46884 | biostudies-arrayexpress

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