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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE218220 | GEO | 2023/08/04

REPOSITORIES: GEO

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Set 2: 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 IQGAP1 KO and parental cells show that IQGAP1 KO alters a specific AS event of the mitochondrial respiratory chain complex I (CI) subunit NDUFS4 and downregulates a subset of CI subunits. In IQGAP1 KO 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 IQGAP1 KO 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 | PXD038331 | Pride

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

2023-08-04 | PXD038314 | Pride

Selective Mitochondrial Respiratory Complex I Subunit Deficiency Causes Tumor Immunogenicity

Project description:Targeting of specific metabolic pathways in tumor cells has the potential to sensitize them to immune-mediated attack. Here we provide evidence for a specific means of mitochondrial respiratory Complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of the CI subunits Ndufs4 and Ndufs6, but not other subunits, induces an immune-dependent tumor growth attenuation in mouse melanoma models. We show that deletion of Ndufs4 induces expression of the transcription factor Nlrc5 and genes in the MHC class-I antigen presentation and processing pathway. This induction of MHC-related genes is driven by an accumulation of pyruvate dehydrogenase-dependent mitochondrial acetyl-CoA downstream of CI subunit deletion. This work provides a novel functional modality by which selective CI inhibition restricts tumor growth, suggesting that specific targeting of Ndufs4, or related CI subunits, increases T-cell mediated immunity and sensitivity to ICB.

2024-10-05 | GSE263533 | GEO

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

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

| PRJNA902759 | ENA

Nuclear IQGAP1 promotes gastric cancer cell growth by altering the splicing of a cell-cycle regulon in co-operation with hnRNPM

Project description:Heterogeneous nuclear ribonucleoproteins (hnRNPs) play a decisive role in alternative splicing, regulating the cell proteome and contributing to human diseases. hnRNPs are nuclear proteins but it is still an open question where they localize in the nucleus and what determines their tethering to nuclear assemblies in response to signals. Here we report that IQGAP1, a cytosolic scaffold protein, localizes in the nucleus of gastric cancer cells acting as a tethering module for hnRNPM as well as other spliceosome components. The IQGAP1-hnRNPM interaction alters, among others, the alternative splicing of ANAPC10 and is required for the response of hnRNPM to heat-induced stress signals. Together, IQGAP1 and hnRNPM promote gastric cancer cell growth while their depletion leads to cell cycle arrest and halts tumour progression. We propose that IQGAP1 localizes in the nucleus and coordinates gastric tumour growth by recruiting, in response to stress-signals, spliceosome components that drive cell cycle progression.

2021-09-09 | GSE146283 | GEO

Ndufs4-knockout mouse with mitochondria complex I inhibitor treatment

Project description:Glucose hypometabolism is one of the major characteristics of Alzheimer's disease (AD). The energy deficiency in AD brain has been at least partially attributed to accelerated mitochondrial dysfunction than normal aging. In earlier publications, we have shown that small molecule mitochondrial complex I inhibitor CP2 facilitated mitochondrial regeneration and rescued mitochondrial deficiency in familial AD mice model APP-PS1. Here in this study, we investigated whether a typical mitochondrial deficiency mouse model could recapitulate molecular expression signatures of AD brain and whether CP2 was able to rescue the AD brain phenotype. Ndufs4 is one of the regulatory subunits of mitochondria complex I. Knockout of Ndufs4 resulted in complex I assembly failure and approximately half mitochondrial function loss. Ndufs4-knockout mice are viable but are short in lifespan (up to about 90 days). This model has been previously used to study Leigh syndrome, a heritable mitochondrial deficiency disease. In this dataset, we performed RNAseq on brains of CP2 treated Ndufs4-knockout mice and examined the expression changes upon CP2 treatment.

2023-12-01 | GSE242286 | GEO

Mitochondrial-nuclear DNA interactions contribute to the regulation of nuclear transcript levels as part of the inter-organelle communication system

Project description:Nuclear and mitochondrial organelles must maintain a communication system. Loci on the mitochondrial genome were recently reported to interact with nuclear loci. To determine whether this is part of a DNA based communication system we used genome conformation capture to map the global network of DNA-DNA interactions between the mitochondrial and nuclear genomes (Mito-nDNA) in Saccharomyces cerevisiae cells grown under three different metabolic conditions. The interactions that form between mitochondrial and nuclear loci are dependent on the metabolic state of the yeast. Moreover, the frequency of specific mitochondrial - nuclear interactions (i.e. COX1-MSY1 and Q0182-RSM7) showed significant reductions in the absence of mitochondrial encoded reverse transcriptase machinery. Furthermore, these reductions correlated with increases in the transcript levels of the nuclear loci (MSY1 and RSM7). We propose that these interactions represent an inter-organelle DNA mediated communication system and that reverse transcription of mitochondrial RNA plays a role in this process. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series.

2013-01-17 | E-GEOD-34132 | biostudies-arrayexpress

The Saccharomyces cerevisiae genome is highly connected by inter- and intra- chromosomal interactions

Project description:Nuclear and mitochondrial organelles must maintain a communication system. Loci on the mitochondrial genome were recently reported to interact with nuclear loci. To determine whether this is part of a DNA based communication system we used genome conformation capture to map the global network of DNA-DNA interactions between the mitochondrial and nuclear genomes (Mito-nDNA) in Saccharomyces cerevisiae cells grown under three different metabolic conditions. The interactions that form between mitochondrial and nuclear loci are dependent on the metabolic state of the yeast. Moreover, the frequency of specific mitochondrial - nuclear interactions (i.e. COX1-MSY1 and Q0182-RSM7) showed significant reductions in the absence of mitochondrial encoded reverse transcriptase machinery. Furthermore, these reductions correlated with increases in the transcript levels of the nuclear loci (MSY1 and RSM7). We propose that these interactions represent an inter-organelle DNA mediated communication system and that reverse transcription of mitochondrial RNA plays a role in this process. Genome Conformation Capture (GCC) has been performed on exponentially growing Saccharomyces cerevisiae cultures in glucose containing media. Paired end sequencing on an Illumina Genome Analyser was performed before the sequences were analysed by the propieatry software Topography 1.19. Inter- and intra- chromosomal interactions were mapped onto the S. cerevisiae S288 genome scaffold.

2013-01-17 | E-GEOD-33073 | biostudies-arrayexpress

Inter- and intra- chromosomal interactions change on a global scale according to the metabolic regime employed by Saccharomyces cerevisiae

Project description:Nuclear and mitochondrial organelles must maintain a communication system. Loci on the mitochondrial genome were recently reported to interact with nuclear loci. To determine whether this is part of a DNA based communication system we used genome conformation capture to map the global network of DNA-DNA interactions between the mitochondrial and nuclear genomes (Mito-nDNA) in Saccharomyces cerevisiae cells grown under three different metabolic conditions. The interactions that form between mitochondrial and nuclear loci are dependent on the metabolic state of the yeast. Moreover, the frequency of specific mitochondrial - nuclear interactions (i.e. COX1-MSY1 and Q0182-RSM7) showed significant reductions in the absence of mitochondrial encoded reverse transcriptase machinery. Furthermore, these reductions correlated with increases in the transcript levels of the nuclear loci (MSY1 and RSM7). We propose that these interactions represent an inter-organelle DNA mediated communication system and that reverse transcription of mitochondrial RNA plays a role in this process. Genome Conformation Capture (GCC) has been performed on exponentially growing Saccharomyces cerevisiae cultures in glycerol lactate or galactose media. Paired end sequencing on an Illumina Genome Analyser was performed before the sequences were analysed by the propieatry software Topography 1.19. Inter- and intra- chromosomal interactions were mapped onto the S. cerevisiae S288 genome scaffold.

2013-01-17 | E-GEOD-33074 | biostudies-arrayexpress

Metabolic Targeting of Cancer by a Ubiquinone Uncompetitive Inhibitor of Mitochondrial Complex I

Project description:SMIP004-7 is a small molecule inhibitor of mitochondrial respiration with selective in vivo anti-cancer activity through a yet unknown molecular target. We demonstrate here that SMIP004-7 targets drug-resistant cancer cells with stem-like features by inhibiting mitochondrial respiration complex I (NADH:ubiquinone oxidoreductase, CI). Instead of affecting the quinone binding site targeted by most CI inhibitors, SMIP004-7 and its cytochrome P450-dependent activated metabolite(s) have an uncompetitive mechanism of inhibition involving a distinct N-terminal region of catalytic subunit NDUFS2 that leads to rapid disassembly of CI. SMIP004-7 and an improved chemical analog selectively engage NDUFS2 in vivo to inhibit the growth of triple negative breast cancer transplants, a response mediated at least in part by boosting CD4+ and CD8+ T cell-mediated immune surveillance. Thus, SMIP004-7 defines an emerging class of ubiquinone uncompetitive CI inhibitors for cell autonomous and microenvironmental metabolic targeting of mitochondrial respiration in cancer.

2019-05-02 | MSV000083740 | MassIVE

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