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Anterograde Regulation of Nuclear-encoded Mitochondrial Genes and FGF21 Signaling by Hepatic Histone Demethylase LSD1 [RNA-seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE161286 | GEO | 2020/11/12

REPOSITORIES: GEO

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Anterograde Regulation of Nuclear-encoded Mitochondrial Genes and FGF21 Signaling by Hepatic Histone Demethylase LSD1

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.

2021-02-01 | GSE145089 | GEO

Anterograde Regulation of Nuclear-encoded Mitochondrial Genes and FGF21 Signaling by Hepatic Histone Demethylase LSD1

Project description:Anterograde Regulation of Nuclear-encoded Mitochondrial Genes and FGF21 Signaling by Hepatic Histone Demethylase LSD1

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Anterograde Regulation of Nuclear-encoded Mitochondrial Genes and FGF21 Signaling by Hepatic Histone Demethylase LSD1 [RNA-seq]

Project description:Anterograde Regulation of Nuclear-encoded Mitochondrial Genes and FGF21 Signaling by Hepatic Histone Demethylase LSD1 [RNA-seq]

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Coordination and assembly of protein complexes encoded across mitochondrial and nuclear genomes is assisted by mtCLPXP in Arabidopsis thaliana

Project description:Protein homeostasis in eukaryotic organelles and their progenitor prokaryotes is regulated by a series of ATP-dependent proteases including the caseinolytic protease complex (ClpXP). In chloroplasts, ClpXP has essential roles in organelle biogenesis and maintenance , but the significance of the plant mitochondrial ClpXP remains unknown and factors that aid coordination of nuclear and mitochondrial encoded subunits for complex assembly in mitochondria await discovery. In this study, we generated knock-out lines of the single copy mitochondrial Clp protease subunit, CLPP2, in Arabidopsis thaliana. They have higher abundance of transcripts from mitochondrial genes encoding OXPHOS protein complexes, while transcripts for nuclear genes encoding other subunits of the same complexes showed no change in transcript abundance. In contrast, the protein abundance of specific nuclear-encoded subunits in OXPHOS complexes I and V increased in knockouts, without accumulation of mitochondrial-encoded counterparts in the same complex. Protein complexes mainly or wholly encoded in the nucleus were unaffected. Analysis of protein import, assembly and function of Complex I revealed that while function was retained, protein homeostasis was disrupted through slower assembly, leading to accumulation of soluble subcomplexes of nuclear-encoded subunits after import. It is proposed that CLPP contributes to the mitochondrial protein degradation network through supporting coordination and assembly of protein complexes encoded across mitochondrial and nuclear genomes.

2019-12-13 | GSE141942 | GEO

Profiling of mRNA localization of nuclear-encoded mitochondrial proteins in zebrafish.

Project description:Current evidence suggests that nuclear-encoded mitochondrial proteins can be locally translated at the mitochondrial surface and co-translationally or post-translationally imported into mitochondria. mRNA localization on the mitochondrial membrane, a prerequisite for localized translation, remains uncharacterized in higher eukaryotic organisms. We employed fractionation-sequencing to profile mitochondria-associated mRNAs in zebrafish larvae. Our transcriptome-wide analysis reveals the localization of mRNAs of only 12% of the nuclear-encoded mitochondrial proteins to the mitochondrial surface, which suggests that post-translational import is the dominant mode of protein import to mitochondria. Additionally, the mRNAs which were localized to the mitochondrial membrane consisted mostly of those encoding proteins involved in mitochondrial dynamics, suggesting their site-specific translation. Finally, we show that the loss of function of the MIA pathway responsible for the post-translational import of a subclass of mitochondrial proteins, triggers mitochondrial localization of mRNAs encoding proteins that are imported to mitochondria via other pathways. Thus, our study suggests that mRNA targeting and localized translation could be relevant in higher eukaryotes to combat stress conditions affecting mitochondrial biogenesis in general.

2023-10-28 | GSE160355 | GEO

Hepatic CPT1A facilitates liver-adipose cross-talk via induction of FGF21

Project description:Hepatosteatosis, defined as excessive intrahepatic lipid accumulation, represents the first step in the development of NAFLD. However, the molecular events directly caused by hepatic lipid build-up, in terms of its impact on liver biology and other peripheral organs, remain unclear. Carnitine palmitoyltransferase 1A (CPT1A) is the rate limiting enzyme for long chain fatty acid beta-oxidation in the liver. Here we utilise hepatocyte-specific Cpt1a knockout (LKO) mice to investigate the physiological consequences of abolishing hepatic long chain fatty acid metabolism to NAFLD and systemic metabolic homeostasis. We show that LKO mice displayed more severe hepatosteatosis but were otherwise protected against diet-induced weight gain, insulin resistance, hepatic ER stress and damage in response to high fat diets. Furthermore, increased energy expenditure accompanied by enhanced adipose tissue browning was observed in LKO mice. Mechanistically, hepatic CPT1A deficiency actives the peroxisome proliferator activator alpha (PPARα)- fibroblast growth factor 21 (FGF21) axis and the elevation of FGF21 contributes to the improved liver pathology and adipose browning in HFD-treated LKO mice. Thus, our study demonstrates that liver with deficient CPT1A expression adopts a healthy steatotic status that protects against HFD-evoked liver damage and potentiates adipose browning in an FGF21-dependent manner. Inhibition of hepatic CPT1A may serve as a viable strategy for the treatment of obesity and NAFLD.

2022-09-10 | GSE183650 | GEO

IQGAP1 mediates the communication between the nucleus and the mitochondria via NDUFS4 alternative splicing

Project description:A constant communication between mitochondria and nucleus ensures cellular homeostasis and adaptation to mitochondrial stress. Anterograde regulatory pathways involving a large number of nuclear-encoded proteins control mitochondrial biogenesis and functions. Such functions are deregulated in cancer, resulting in proliferative advantages for cancer cells, aggressive disease and therapeutic resistance. Transcriptional networks controlling the nuclear-encoded mitochondrial genes are known, however alternative splicing (AS) regulation has not been implicated in this communication. Here, we show that IQGAP1, a scaffold protein that regulates AS of distinct gene subsets in gastric cancer cells, participates in AS regulation that strongly affects mitochondrial respiration. Combined proteomic and RNA-seq analyses of IQGAP1KO and parental cells show that IQGAP1KO alters a specific AS event of the mitochondrial respiratory chain complex I (CI) subunit NDUFS4 and downregulates a subset of CI subunits. In IQGAP1KO cells, CI intermediates accumulate resembling assembly deficiencies observed in patients with Leigh syndrome bearing NDUFS4 mutations. Mitochondrial CI activity is significantly lower in KO compared to parental cells, while exogenous expression of IQGAP1 reverses mitochondrial defects of IQGAP1KO cells. Our work sheds light to a novel facet of IQGAP1 in mitochondrial quality control that involves fine-tuning of CI activity through AS regulation in gastric cancer.

2023-08-04 | GSE218220 | GEO

Coordination and assembly of protein complexes encoded across mitochondrial and nuclear genomes is assisted by mtCLPP in Arabidopsis thaliana.

Project description:Protein homeostasis in eukaryotic organelles and their progenitor prokaryotes is regulated by a series of proteases including the caseinolytic protease (CLPP). CLPP has essential roles in chloroplast biogenesis and maintenance, but the significance of the plant mitochondrial CLPP remains unknown and factors that aid coordination of nuclear and mitochondrial encoded subunits for complex assembly in mitochondria await discovery. We generated knock-out lines of the single copy mitochondrial CLP protease subunit, CLPP2, in Arabidopsis thaliana. Mutants have higher abundance of transcripts from mitochondrial genes encoding OXPHOS protein complexes, while transcripts for nuclear genes encoding other subunits of the same complexes showed no change in transcript abundance. In contrast, the protein abundance of specific nuclear-encoded subunits in OXPHOS complexes I and V increased in knockouts, without accumulation of mitochondrial-encoded counterparts in the same complex. Protein complexes mainly or entirely encoded in the nucleus were unaffected. Analysis of protein import, assembly and function of Complex I revealed that while function was retained, protein homeostasis was disrupted through slower assembly, leading to accumulation of soluble subcomplexes of nuclear-encoded subunits. Therefore, CLPP2 contributes to the mitochondrial protein degradation network through supporting coordination and assembly of protein complexes encoded across mitochondrial and nuclear genomes.

2020-09-14 | PXD016746 | Pride

LARP4 Is an RNA-Binding Protein That Binds Nuclear-Encoded Mitochondrial mRNAs To Promote Mitochondrial Function

Project description:Mitochondrial associated RNA-binding proteins (RBPs) have emerged as key contributors to mitochondrial biogenesis and homeostasis. With few examples described, we set out to identify RBPs that post-transcriptionally regulate nuclear-encoded mitochondrial mRNAs (NEMmRNAs). Our analysis of RNA-target sets of RBPs made available by ENCODE identified several RBPs with a preference for binding NEMmRNAs, of which we selected LARP4, a La RBP family member, for further study. We show that LARP4’s RNA-target set is particularly enriched in mRNAs that encode for respiratory chain complex proteins (RCCPs) and mitochondrial ribosome proteins (MRPs) across multiple human cell lines. CRISPR knockout cells in conjunction with quantitative proteomics show that protein levels of RCCPs and MRPs are significantly reduced upon loss of LARP4. Furthermore, we show that LARP4 depletion reduces mitochondrial function, and this phenotype is ameliorated by LARP4 re-expression. Our findings shed light onto a novel function for LARP4 as an RBP that binds to NEMmRNAs to promote mitochondrial respiratory function.

2024-03-11 | GSE193134 | GEO

Differential gene expression analysis in liver, inguinal white adipose tissue (iWAT), skeletal muscle, and hypothalamus of mice with liver-specific Crif1 deficiency

Project description:CR6-interacting factor-1 (CRIF1) interacting with large mitoribosome subunits is essential for the maturation and insertion of oxidative phosphorylation (OxPhos) polypeptides into the mitochondrial inner membrane. Recently, it has reported that the genetic ablation of Crif1 in a tissue-specific manner results in mitochondrial stress response (MSR) including mitochondrial unfolded protein response (UPRmt). In this study, we aim to obtain a comprehensive understanding of systemic energy metabolism in response to hepatic mitochondrial dysfunction. Through the liver-specific Crif1 deficient mice (LKO), we explore the adaptive response not only in the liver but also in inguinal white adipose tissue (iWAT). Moreover, RNA sequencing in liver, iWAT, skeletal muscle, and hypothalamus suggest that hepatic mitochondrial dysfunction enhance metabolic pathways, including glycolysis, fatty acid elongation and degradation, and 1C metabolism in liver and insulin signaling in iWAT. RNA sequencing also suggests that hepato-mitokines, GDF15 and FGF21 are highly increased in liver of LKO mice. To identify the role of hepato-mitokines, we generate double knockout mice (LKO/Gdf15-/- and LKO/Fgf21-/-), suggesting that GDF15 is responsible for the regulation of the body and fat mass and FGF21 has a critical role for the insulin sensitivity and energy expenditure in this mice.

2021-03-10 | GSE149553 | GEO

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