Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA389251 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:In animals the organization of the compact mitochondrial genome and lack of introns have necessitated a unique mechanism for RNA processing. To date the regulation of mitochondrial RNA processing and its importance for ribosome biogenesis and energy metabolism are not clear. To understand the in vivo role of the endoribonuclease component of the RNase P complex, MRPP3, we created conditional knockout mice. Here we show that MRPP3 is essential for life, and heart and skeletal muscle-specific knockout leads to a cardiomyopathy early in life, indicating that it is the only RNase P enzyme in mitochondria. We show that RNA processing is required for the biogenesis of the respiratory chain and mitochondrial function. Transcriptome-wide parallel analyses of RNA ends (PARE) and RNA-Seq enabled us to identify the in vivo cleavage sites of RNase P. Cleavage of the 5â² tRNA ends precedes 3â² end processing in vivo and is required for the correct biogenesis of the mitochondrial ribosomal subunits and mitoribosomal proteins that are differentially stabilized or degraded in the absence of mature rRNAs. Finally we identify that large mitoribosomal proteins can form a subcomplex on a precursor mt-RNA containing the 16S rRNA indicating that mitoribosomal biogenesis proceeds co-transcriptionally. Taken together our data show that RNA processing links transcription to translation via assembly of the mitoribosome. Total RNA was isolated from heart tissue from 11 week old control (Mrpp3loxP/loxP) and Mrpp3 knockout mice (Mrpp3loxP/loxP, +/Ckmm), TruSeq libraries produced in triplicate, sequenced and analysed for differential expression. Mitochondrial RNA was isolated from heart tissue from 11 week old control (Mrpp3loxP/loxP) and Mrpp3 knockout mice (Mrpp3loxP/loxP, +/Ckmm), PARE libraries produced in triplicate and sequenced for analysis of mitochondrial RNA processing.
2016-08-04 | E-GEOD-83471 | biostudies-arrayexpress
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2018-08-20 | GSE111227 | GEO
Project description:The molecular roles of the dually targeted ElaC domain protein 2 (ELAC2) during nuclear and mitochondrial RNA processing in vivo have not been distinguished. We generated conditional knockout mice of ELAC2 to identify that it is essential for life and its activity is non-redundant. Heart and skeletal muscle-specific loss of ELAC2 causes dilated cardiomyopathy and premature death at 4 weeks. Transcriptome-wide analyses of total RNAs, small RNAs, mitochondrial RNAs and miRNAs identified the nuclear and mitochondrial molecular targets of ELAC2 in vivo. We show that ELAC2 is required for processing of nuclear and mitochondrial tRNAs and for the balanced maintenance of C/D box snoRNAs, a new class of tRNA fragments, and miRNAs. We identify that correct biogenesis of regulatory non-coding RNAs is essential for both cytoplasmic and mitochondrial protein synthesis as well as the assembly of mitochondrial ribosomes and cytoplasmic polysomes. Taken together our data show that nuclear tRNA processing is required for the balanced production of snoRNAs and miRNAs for gene expression and that 3′ tRNA processing follows 5′ tRNA processing but nevertheless is an essential step in the production of all mature mitochondrial RNAs and the majority of nuclear tRNAs.
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Project description:The molecular roles of the dually targeted ElaC domain protein 2 (ELAC2) during nuclear and mitochondrial RNA processing in vivo have not been distinguished. We generated conditional knockout mice of ELAC2 to identify that it is essential for life and its activity is non-redundant. Heart and skeletal muscle-specific loss of ELAC2 causes dilated cardiomyopathy and premature death at 4 weeks. Transcriptome-wide analyses of total RNAs, small RNAs, mitochondrial RNAs and miRNAs identified the nuclear and mitochondrial molecular targets of ELAC2 in vivo. We show that ELAC2 is required for processing of nuclear and mitochondrial tRNAs and for the balanced maintenance of C/D box snoRNAs, a new class of tRNA fragments, and miRNAs. We identify that correct biogenesis of regulatory non-coding RNAs is essential for both cytoplasmic and mitochondrial protein synthesis as well as the assembly of mitochondrial ribosomes and cytoplasmic polysomes. Taken together our data show that nuclear tRNA processing is required for the balanced production of snoRNAs and miRNAs for gene expression and that 3′ tRNA processing follows 5′ tRNA processing but nevertheless is an essential step in the production of all mature mitochondrial RNAs and the majority of nuclear tRNAs.
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Project description:In animals the organization of the compact mitochondrial genome and lack of introns have necessitated a unique mechanism for RNA processing. To date the regulation of mitochondrial RNA processing and its importance for ribosome biogenesis and energy metabolism are not clear. To understand the in vivo role of the endoribonuclease component of the RNase P complex, MRPP3, we created conditional knockout mice. Here we show that MRPP3 is essential for life, and heart and skeletal muscle-specific knockout leads to a cardiomyopathy early in life, indicating that it is the only RNase P enzyme in mitochondria. We show that RNA processing is required for the biogenesis of the respiratory chain and mitochondrial function. Transcriptome-wide parallel analyses of RNA ends (PARE) and RNA-Seq enabled us to identify the in vivo cleavage sites of RNase P. Cleavage of the 5′ tRNA ends precedes 3′ end processing in vivo and is required for the correct biogenesis of the mitochondrial ribosomal subunits and mitoribosomal proteins that are differentially stabilized or degraded in the absence of mature rRNAs. Finally we identify that large mitoribosomal proteins can form a subcomplex on a precursor mt-RNA containing the 16S rRNA indicating that mitoribosomal biogenesis proceeds co-transcriptionally. Taken together our data show that RNA processing links transcription to translation via assembly of the mitoribosome.
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Project description:Mitochondrial and peroxisomal anchored protein ligase (MAPL) is a dual ubiquitin and small ubiquitin-like modifier (SUMO) ligase with context-dependent roles in mitochondrial quality control, cell death and inflammation in cultured cell lines. Here, we show that physiological MAPL function in organismal context converges on metabolic control, as knockout mice are viable, but lean, highly insulin sensitive, and protected from high fat-diet induced obesity. MAPL loss leads to liver-specific activation of the integrated stress response, inducing secretion of starvation hormone FGF21, known to drive the reduction of white fat stores and promote insulin sensitivity. During aging, MAPL knockout mice developed fully penetrant spontaneous hepatocellular carcinoma, which is pathologically distinct from NASH/NAFLD-linked liver cancers. Mechanistically, proximity interaction analysis revealed the peroxisomal bile acid transporter ABCD3 (PMP70) as a primary MAPL interacting partner, SUMOylated in a MAPL-dependent manner. MAPL knockout leads to increased bile acid production coupled with defective regulatory feedback in liver in vivo and in isolated primary hepatocytes, suggesting cell-autonomous function. Together, our findings establish MAPL function as a central regulator of bile acid synthesis whose loss led to the profound disruption of bile acid feedback mechanisms. The unique metabolic consequences of MAPL loss in liver, along with evidence of tumor suppression through the regulation of cell survival pathways, lead ultimately to a new animal model of spontaneous hepatocellular carcinoma.
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Project description:Mitochondrial dynamics and mitophagy are intimately linked physiological processes that are essential for cardiac homeostasis. Here we show that cardiac Klf9 is dysregulated in human and rodent cardiomyopathy. Young adult global Klf9-knockout mice displayed hypertrophic cardiomyopathy that was characterized by depressed systolic function, increased left ventricular mass and pulmonary congestion. Klf9 knockout led to mitochondrial disarray and fragmentation in cardiomyocytes. Biochemical analysis confirmed that mitochondrial respiratory function was impaired in Klf9-knockout cardiomyocytes, with reduced myocardial ATP levels and elevated ROS. Furthermore, cardiac-specific Klf9-deficient mice phenocopied global Klf9-knockout mice, suggesting that cardiac Klf9 is essential for mitochondrial homeostasis and heart function. Moreover, cardiac Klf9 deficiency inhibited mitophagy induced by angiotensin II (ANGII), thereby leading to accumulation of dysfunctional mitochondria and acceleration of heart failure in mice in response to ANGII treatment. In contrast, cardiac-specific Klf9 transgene improved cardiac systolic function via promoting mitophagy in mice in response to ANGII treatment. Molecular mechanism studies indicated that Klf9 knockout decreased the expression of PGC-1α and its target genes involved in mitochondrial energy metabolism. Moreover, Klf9 controlled the expression of Mfn2 by directly binding to its promoter region, thereby regulating mitochondrial dynamics and mitophagy. Finally, we performed Mfn2 rescue experiments in Klf9-CKO mice and found that AAV-mediated Mfn2 rescue in heart improved cardiac mitochondrial and systolic function in Klf9-CKO mice treated with or without ANGII. Thus, Klf9 integrates cardiac energy metabolism, mitochondrial dynamics and mitophagy. Modulating Klf9 activity may have therapeutic potential in the treatment of heart failure.
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Project description:Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving more than one thousand nuclear-encoded proteins. Transcriptional networks controlling the nuclear-encoded mitochondrial genes remain fully elucidated. Here we show that histone demethylase LSD1 knockout from adult mouse liver (LSD1-LKO) reduces one-third of all nuclear-encoded mitochondrial genes and decreases mitochondrial biogenesis and function. ChIP-seq analysis shows that LSD1 and LSD1-targeted H3K4me2 modulate the expression of mitochondrial genes in liver.
2020-11-12 | GSE161286 | GEO
Project description:Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving more than one thousand proteins encoded by nuclear genome. Transcriptional networks controlling the nuclear-encoded mitochondrial genes remain elucidated. Here we show that histone demethylase LSD1 knockout from adult mouse liver (LSD1-LKO) reduces one-third of all nuclear-encoded mitochondrial genes and decreases mitochondrial biogenesis and function. LSD1-modulated histone methylation epigenetically regulates nuclear-encoded mitochondrial genes. Furthermore, LSD1 targets methylation of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), the rate-limiting enzyme for nuclear NAD+ synthesis. Hepatic LSD1 knockout reduces NAD+-dependent Sirt1 and Sirt7 deacetylase activity, leading to hyperacetylation and hypofunctioning of GABP and PGC-1, the major transcriptional factor/cofactor for nuclear-encoded mitochondrial genes. Despite the reduced mitochondrial function, LSD1-LKO mice are protected from diet-induced hepatic steatosis and glucose intolerance, partially due to induction of hepatokine FGF21. Thus, LSD1 orchestrates a core regulatory network involving epigenetic modifications and NAD+ synthesis to control mitochondrial function and hepatokine production.
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