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Recessive mutation in EXOSC3 associates with mitochondrial dysfunction and pontocerebellar hypoplasia

ABSTRACT: Recessive mutations in EXOSC3, encoding a subunit of the human RNA exosome complex, cause Pontocerebellar hypoplasia type 1b (PCH1B). We report a boy with severe muscular hypotonia, psychomotor retardation, progressive microcephaly, and cerebellar atrophy. Biochemical abnormalities comprised mitochondrial Complex I and PDHc deficiency. Whole exome sequencing uncovered a known EXOSC3-mutation p.(D132A) as the underlying cause. In patient fibroblasts, >50% of the EXOSC3 protein was trapped in the cytosol. mtDNA-copy numbers in muscle were reduced to 40%, but mutations in the mtDNA and nuclear mitochondrial genes were excluded. RNA-seq of patient muscle showed highly increased mRNA-copy numbers, especially for genes encoding structural subunits of OXPHOS-complexes I, III, and IV, possibly due to reduced degradation by a dysfunctional exosome complex. This is the first case of mitochondrial dysfunction associated with an EXOSC3 mutation, which expands the phenotypic spectrum of PCH1B. We discuss the links between exosome and mitochondrial dysfunction.

ORGANISM(S): Homo sapiens

PROVIDER: GSE99715 | GEO | 2017/08/22

SECONDARY ACCESSION(S): PRJNA389402

REPOSITORIES: GEO

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RNA exosome mutations in pontocerebellar hypoplasia alter ribosome biogenesis and p53 levels

Project description:The eukaryotic RNA exosome is a ubiquitously expressed complex of nine core proteins (EXOSC1-9) and associated nucleases responsible for RNA processing and degradation. Autosomal recessive mutations in EXOSC3, EXOSC8, EXOSC9 and the exosome cofactor RBM7 cause pontocerebellar hypoplasia and motor neuronopathy. To understand the importance of the exosome in neurodegeneration, we investigated the consequences of exosome mutations on RNA metabolism and cellular survival in zebrafish and human cell models. We observed that levels of mRNAs encoding p53 and ribosome biogenesis factors are upregulated in zebrafish lines with homozygous mutations of exosc8 or exosc9, respectively. In addition, exosome deficiency leads to increased levels of multiple non-coding RNAs (e.g. tRNAs, snoRNAs, scaRNAs). Consistent with higher p53 levels, mutant zebrafish have a reduced head size, smaller brain and cerebellum caused by an increased number of apoptotic cells during development. Downregulation of EXOSC9 in human cells leads to p53 protein stabilisation and G2/M cell cycle arrest. The work provides explanation for the pathogenesis of exosome-related disorders and highlights the link between exosome function, ribosome biogenesis and p53-dependent signalling.

2020-05-30 | GSE151452 | GEO

A Budding Yeast Model for Human Disease Mutations in the EXOSC2 Cap Subunit of the RNA Exosome

Project description:RNA exosomopathies, a growing family of tissue-specific diseases, are linked to missense mutations in genes encoding the structural subunits of the conserved 10-subunit exoribonuclease complex, the RNA exosome. Such mutations in the cap subunit gene EXOSC2 cause the novel syndrome SHRF (Short stature, Hearing loss, Retinitis pigmentosa and distinctive Facies). In contrast, exosomopathy mutations in the cap subunit gene EXOSC3 cause pontocerebellar hypoplasia type 1b (PCH1b). Though having strikingly different disease pathologies, EXOSC2 and EXOSC3 exosomopathy mutations result in amino acid substitutions in similar, conserved domains of the cap subunits, suggesting that these exosomopathy mutations have distinct consequences for RNA exosome function. We generated the first in vivo model of the SHRF pathogenic amino acid substitutions using budding yeast by introducing the EXOSC2 mutations in the orthologous S. cerevisiae gene RRP4. The resulting rrp4 mutant cells have defects in cell growth and RNA exosome function. We detect significant transcriptomic changes in both coding and non-coding RNAs in the rrp4 variant, rrp4-G226D, which models EXOSC2 p.Gly198Asp. Comparing this rrp4-G226D mutant to the previously studied S. cerevisiae model of EXOSC3 PCH1b mutation, rrp40-W195R, reveals that these mutants have disparate effects on certain RNA targets, providing the first evidence for different mechanistic consequences of these exosomopathy mutations. Congruently, we detect specific negative genetic interactions between RNA exosome cofactor mutants and rrp4-G226D but not rrp40-W195R. These data provide insight into how SHRF mutations could alter the function of the RNA exosome and allow the first direct comparison of exosomopathy mutations that cause distinct pathologies.

2020-12-14 | GSE163106 | GEO

Tfam Knockdown Results in Reduction of mtDNA Copy Number, OXPHOS Deficiency and Abnormalities in Zebrafish Embryos

Project description:High mitochondrial DNA (mtDNA) copy numbers are essential for oogenesis and embryogenesis and correlate with fertility of oocytes and viability of embryos. To understand the pathology and mechanisms associated with low mtDNA copy numbers, we knocked down mitochondrial transcription factor A (Tfam), a regulator of mtDNA replication, during early zebrafish development. Reduction of Tfam using a splice-modifying morpholino (MO) resulted in a 42%±4% decrease in mtDNA copy number in embryos at 4 days post fertilization (4 dpf). Morphant embryos displayed abnormal development of the eye, brain, heart and muscle, as well as a 50%±11% decrease in ATP production. Transcriptome analysis revealed a decrease in protein-encoding transcripts from the heavy strand of the mtDNA. In addition, various RNA translation pathways were increased, indicating an upregulation of nuclear and mitochondria-related translation. The developmental defects observed were supported by a decreased expression of pathways related to eye development and haematopoiesis. The increase in mRNA translation might serve as a compensation mechanism, but appears insufficient during prolonged periods of mtDNA depletion, highlighting the importance of high mtDNA copy numbers for early development in zebrafish.

2020-03-10 | GSE146696 | GEO

Homo sapiens

Project description:Recessive mutation in EXOSC3 associates with mitochondrial dysfunction and pontocerebellar hypoplasia

| PRJNA389402 | ENA

The RNA helicase DDX1 associates with the nuclear RNA exosome and modulates R-loops [RNA-seq]

Project description:The RNA exosome is a ten-subunit complex that mediates both RNA processing and degradation. This complex is evolutionarily conserved, ubiquitously expressed, and required for fundamental cellular functions, including rRNA processing. The RNA exosome plays many roles in regulating gene expression and protecting the genome, including modulating the accumulation of R-loops at sites of transcription. The RNA exosome interacts with specific target RNAs for decay or processing by interacting proteins termed cofactors. Attributing to the essential function of the RNA exosome for processes critical in all cells, such as production of mature rRNA, missense mutations in structural subunit genes of this complex cause neurological diseases. One possibility for why point mutations cause neurological diseases is that the RNA exosome partners with cell- or tissue-specific protein cofactors. Here, we employed a murine neuronal cell line (N2A) and performed immunoprecipitation of the RNA exosome subunit, EXOSC3, followed by mass spectrometry to obtain a snapshot of the RNA exosome interactome. We validated an interaction with DDX1, a putative RNA helicase. DDX1 plays roles in double-strand break repair, rRNA processing, and RNA metabolism. To explore shared functions of EXOSC3 and DDX1, we investigated the interaction after inducing DNA damage, and performed DNA/RNA immunoprecipitation followed by sequencing (DRIP-Seq) and RNA-seq on N2A cells depleted of either EXOSC3 or DDX1. These findings suggest that EXOSC3 and DDX1 function together in the absence of severe DNA damage to modulate spontaneous events such as RNA-DNA hybrid (R-loop) formation.

2024-02-12 | GSE230120 | GEO

The RNA helicase DDX1 associates with the nuclear RNA exosome and modulates R-loops [DRIP-seq]

2024-02-12 | GSE230115 | GEO

The nuclear RNA exosome is co-opted to enhance host:viral RNA hybrids that propel influenza virus ribogenesis and infectivity

Project description:The nuclear RNA exosome is an essential multi-subunit complex that controls RNA homeostasis. Congenital mutations in exosome genes are associated with neurodegenerative diseases. Here, we show that transient depletion of nuclear RNA exosome subunits in epithelial cells inhibits influenza virus replication. Similarly, viral biogenesis was suppressed in cells derived from mice with conditional ablation of the RNA exosome subunit Exosc3. Furthermore, patient-derived cells with a congenital EXOSC3 mutation were less susceptible to influenza virus infection. Using proteomics and next generation sequencing during infection, we show that the viral polymerase complex (PA, PB2, PB1) co-opts the nuclear RNA exosome complex and cellular RNAs en route to 3’ end degradation. Mechanistically, the nuclear RNA exosome coordinates the initial steps of viral transcription with RNAPII at host promoters. Exosome deficiency uncouples chromatin targeting of the viral polymerase complex and the formation of cellular:viral RNA hybrids, which are essential RNA intermediates that license transcription of antisense genomic viral RNAs. Overall, we discovered a critical nexus between an essential component of the influenza virus (polymerase) and an essential component of the cell (exosome), alteration of which leads to breakage of host-pathogen symmetry and a lose-lose scenario (viral impairment and neurodegeneration).

2017-05-08 | GSE96677 | GEO

Drosophila CNS mitochondrial DNA dysfunction microarray

Project description:Mitochondrial DNA (mtDNA) encodes essential components of the respiratory chain and loss of mtDNA leads to mitochondrial dysfunction and neurodegeneration. Mitochondrial transcription factor A (TFAM) is an essential component of mtDNA replication and a regulator of mitochondrial copy number in cells. Studies have shown that TFAM knockdown leads to mitochondrial dysfunction and respiratory chain deficiencies. ATP synthase is Complex V of the mitochondrial respiratory chain. It is driven by a proton gradient between the intermembrane space and the mitochondrial matrix and generates the majority of cellular ATP. The knockdown of coupling factor 6 (Cf6), one of the components of the proton channel F0, causes dysfunction in the complex, leading to mitochondrial dysfunction and respiratory chain deficiencies. Using gene expression analysis, we aimed to investigate the effects of mtDNA dysfunction in the CNS at the molecular level.

2013-12-20 | GSE53509 | GEO

mtDNA breaks compromise mitochondrial membrane ultrastructure and trigger an integrated stress response

Project description:Mitochondrial DNA (mtDNA) breaks are deleterious lesions that lead to degradation of mitochondrial genomes and subsequent reduction in mtDNA copy number. The signaling pathways activated in response to mtDNA damage remain ill-defined. Using mitochondrial targeted restriction enzymes, we show that cells with mtDNA breaks exhibit reduced respiratory complexes, loss of membrane potential, and mitochondrial protein import defect. Furthermore, mtDNA damage activates the integrated stress response (ISR) through phosphorylation of eIF2α by the OMA1-DELE1-HRI pathway. Electron microscopy reveals concomitant defects in mitochondrial membranes and cristae ultrastructure. Notably, inhibition of the ISR exacerbates mitochondrial defects and delays the recovery of mtDNA copy number, thereby implicating this stress response in mitigating mitochondrial dysfunction following mtDNA damage. Last, we provide evidence suggesting that ATAD3A, a membrane-anchored protein that interacts with nucleoids, relays the signal from mtDNA breaks to the inner mitochondrial membrane. Altogether, our study fully delineates the sequence of events linking damaged mitochondrial genomes with the cytoplasm and uncovers an unanticipated role for the ISR in response to mitochondrial genome instability.

2022-10-04 | GSE214512 | GEO

Drosophila CNS mitochondrial DNA dysfunction microarray

Project description:Mitochondrial DNA (mtDNA) encodes essential components of the respiratory chain and loss of mtDNA leads to mitochondrial dysfunction and neurodegeneration. Mitochondrial transcription factor A (TFAM) is an essential component of mtDNA replication and a regulator of mitochondrial copy number in cells. Studies have shown that TFAM knockdown leads to mitochondrial dysfunction and respiratory chain deficiencies. Using gene expression analysis, we aimed to investigate the effects of mtDNA dysfunction in the CNS at the molecular level. We used microarray analysis to investigate gene expression in cases of mitochondrial dysfunction in the CNS. RNA was purified from the late third instar larval CNS from control larvae, or larvae over-expressing mitochondrial transcription factor A (TFAM) in post-mitotic neurons using the neuron specific driver nsyb-Gal4. Three replicates are included for each condition.

2013-12-20 | E-GEOD-53509 | biostudies-arrayexpress

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