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Mitochondrial Proteostatic Stress Induces Aggrephagy to Triage Unimported Proteins

ABSTRACT: We report the results of overexpression of the wildtype and mutant ANT1 (SLC25A4) gene in human embryonic kidney 293T (HEK293T) cells from the cytomegalovirus (CMV) promoter. Libraries were prepared from three independent replicates per condition using stranded RNA sequencing and run at 2 x 75 read length at a targeted output of 60 million paired-end reads per sample. We found only a limited number of nuclear genes whose expression is altered by wildtype ANT1-overexpression. Among the most upregulated genes is the zinc-finger proteins Egr1, a transcriptional factor with diverse cellular functions, including the repression of genes encoding mitochondrial inner membrane protein. The upregulation of EGR1 likely serves as a retrograde mechanism to reduce protein loading on the IMM and to alleviate mPOS. Overexpression of the triple and quadruple mutant alleles altered the expression of 206 and 560 genes, respectively, with 32 commonly up-regulated in both. These include EGR1, ZCCHC12 and SFPQ, which were also upregulated in cells overexpressing the wild-type ANT1. The 32 up-regulated genes are involved in functions including RNA-processing, autophagy/intracellular structure/trafficking, transcriptional control, ribosomal biogenesis/translational control, chaperones/proteasomal function and mitochondrial biogenesis. Upstream regulator analysis subsequently revealed 42 pathways predicted to be either activated or inhibited by these genes, including PPARGC1A, ATF4, Heat Shock Factor 1 (HSF1), mechanistic Target of Rapamycin (mTOR), Myc, EGFR and HMGA1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE108622 | GEO | 2018/12/29

REPOSITORIES: GEO

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Cytosolic Proteostatic Adaptation to Mitochondrial Stress Causes Progressive Muscle Wasting

Project description:Purpose: Muscle wasting (or atrophy) occurs in primary neuromuscular diseases and during aging, with sarcopenia affecting 35.4% and 75.5% of women and man over 60 years of age. Mitochondrial dysfunction is proposed to contribute to muscle wasting. Here, we show that chronic adaptation to mitochondrial Precursor Over-accumulation Stress (mPOS) causes muscle wasting. mPOS is a newly discovered cell stress mechanism caused by the saturation or damage of the mitochondrial protein import machinery, which consequently leads to the toxic accumulation of precursor proteins in the cytosol. Methods: We generated transgenic mice with a two-fold increase of Ant1, an adenine nucleotide translocase involved in ATP/ADP exchange on the inner mitochondrial membrane (IMM). We found that these animals progressively lose muscle mass. At two years of age, the skeletal muscle becomes barely quantifiable, without affecting the overall lifespan. We then performed whole-transcriptome RNA-sequencing on skeletal muscle samples of male and female mice at 6 months of age. Results: After alignment and quantification, we show that the ANT1-transgenic muscles have a drastically remodeled transcriptome that represses protein synthesis, and stimulates proteasomal function, autophagy, lysosomal amplification and Gadd45a-signaling. These four processes are all known to promote muscle wasting. Conclusions: These results suggest that chronic proteostatic adaptation to mPOS is a robust mechanism of muscle wasting, and it leads to or depends in part on a robust set of transcriptional adaptations. This finding may help the understanding of how mitochondria contribute to muscle wasting during aging. It may also have implications for diseases that are associated with ANT1 overexpression.

2019-08-09 | GSE135584 | GEO

Mitochondrial protein import clogging as a mechanism of disease

Project description:Mitochondrial biogenesis requires the import of >1,000 mitochondrial preproteins from the cytosol. Most studies on mitochondrial protein import are focused on the core import machinery. Whether and how the biophysical properties of substrate preproteins affect overall import efficiency is underexplored. Here, we show that protein traffic into mitochondria can be disrupted by amino acid substitutions in a single substrate preprotein. Pathogenic missense mutations in adenine nucleotide translocase 1 (Ant1), and its yeast homolog Aac2, cause the protein to accumulate along the protein import pathway, thereby obstructing general protein translocation into mitochondria. This impairs mitochondrial respiration, cytosolic proteostasis and cell viability independent of Ant1’s nucleotide transport activity. The mutations act synergistically, as double mutant Aac2/Ant1 cause severe clogging primarily at the Translocase of the Outer Membrane (TOM) complex. This confers extreme toxicity in yeast. In mice, expression of a super-clogger Ant1 variant led to neurodegeneration and an age-dependent dominant myopathy that phenocopy Ant1-induced human disease, suggesting clogging as a mechanism of disease. More broadly, this work implies the existence of uncharacterized amino acid requirements for mitochondrial carrier proteins to avoid clogging and subsequent disease.

2023-03-17 | GSE227295 | GEO

EGR1 regulation in human bone marrow stromal cells

Project description:Human bone marrow stromal cells (BMSCs) are key elements of the hematopoietic environment and they play a central role in bone and bone marrow physiology. However, how key BMSC functions are regulated is largely unknown. We analyzed the role of the immediate early response transcription factor EGR1 as key BMSC regulator and found that EGR1 was highly expressed in prospectively-isolated primary BMSCs, downregulated upon culture, and lower in non-CFU-F-containing CD45neg BM cells. Furthermore, EGR1 expression was lower in proliferative regenerating adult and fetal primary cells compared to adult steady-state BMSCs. Accordingly, EGR1 overexpression markedly decreased BMSC proliferation but considerably improved hematopoietic stroma support function as indicated by an increased production of transplantable CD34+CD90+ hematopoietic stem cells in expansion co-cultures. The improvement of BMSC stroma support function was mediated by increased expression of hematopoietic supporting genes, such as VCAM1 and CCL28. On the other hand, EGR1 knockdown increased ROS-mediated BMSC proliferation, and clearly reduced BMSC hematopoietic stroma support potential. These findings thus show that EGR1 is a key BMSC transcription factor with a dual role in regulating proliferation and hematopoietic stroma support function that is controlling a genetic program to coordinate the specific functions of BMSC in their different biological contexts.

2019-06-27 | PXD011767 | Pride

The role of Egr1 and FosB in the 6 hour injury response

Project description:This trancriptome analysis reports genes that are differentially expressed in wildtype (WT) lens epithelial cells (LEC) between 6 hours and zero hours after injury, and between Egr1 (E1) or FosB (FB) null LEC and wildtype LEC at zero hours (0H) and at 6 hours (6H) after injury.

2022-11-16 | GSE206574 | GEO

Analysis of transcript abundances in Ectocarpus life cycle mutants

Project description:The aim of this experiment was to compare transcript abundances in parthenotes (i.e. organisms derived by parthenogenetic development of gametes) of two life cycle mutants of the brown alga Ectocarpus siliculosus with transcript abundances in the wild type sporophyte and gametophyte generations. This is of interest because the two mutations, immediate upright (imm) and ouroboros (oro), cause partial and almost complete hometic conversion, respectively, of the sporophyte into the gametophyte. imm parthenotes exhibit gametophyte-like morphology during early development but remain sporophytes in functional terms (they do not produce gametes) whereas oro parthenotes behave as functional gametophytes and are morphologically indistinguishable from gametophytes apart from the appearance some minor sporophyte-like features very early in development in some individuals. To minimise genetic background effects the samples for this experiment were derived from a segregating population derived from an imm/IMM oro/ORO sporophyte. Four classes of gametophyte were derived from this sporophyte were IMM/ORO (wild type), imm/ORO, IMM/oro and imm/oro. Parthenomes were bulked to provide a wild type sporophyte sample, samples corresponding to the two individual mutants, plus the double mutant. A wild type gametophyte sample was also compared for comparison. Hybridisations with cDNA derived from these five samples were carried out using a NimbleGen expressed-sequence-tag-(EST-)based microarray carrying probes corresponding to 10,600 of the 16,256 genes identified in the Ectocarpus genome.

2012-01-14 | E-MTAB-485 | biostudies-arrayexpress

EGR1 is a gatekeeper of inflammatory enhancers in human macrophages

Project description:We investigated the function of EGR1 in macrophage differentiation and activation. We generated EGR1 CHIP-seq and CUT-and-RUN data during GM-CSF induced macrophage differentiation, paired with ATAC-seq. We performed RNA-seq and CHIP-seq for H3K27ac in EGR1-depleted differentiated macrophages. Finally we generated RNA-seq data in activated macrophages with EGR1 overexpression.

2020-01-01 | GSE136216 | GEO

Time course analysis of genes regulated by E. coli sigma 32 (rpoH) after overexpression

Project description:DNA microarray analysis of genes regulated by the alternative sigma factor, sigma 32 (rpoH). Sigma 32-dependent genes were initially identified by comparing a wild type (wt) E. coli K-12 strain that has a low level of sigma 32, with a strain over-expressing sigma 32 (following induction of rpoH from an inducible promoter by IPTG). We monitored changes in gene expression in 4 separate time-courses. Because sigma 32 is negatively regulated, its activity decreases 10 min after overexpression. Consequently, to identify genes regulated by sigma 32 we analyzed the expression data for 10 min after overexpression using SAM (Statistical Analysis of Microarrays). We identified 105 genes organized in 66 separate transcription units. This study is detailed in Nonaka et al 2006 (submitted). Keywords: time course

2006-03-06 | GSE4321 | GEO

Role of ANT1 in pulmonary fibrosis

Project description:Crispr KO of ANT1 in Beas2b cells versus control cells were treated with media or bleomycin

2023-10-03 | GSE244305 | GEO

Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol

Project description:The vast majority of the mitochondrial proteome originates from nuclear genes and is transported into the organelle after synthesis in the cytosol. Complex machineries, which maintain the specificity of protein import and sorting, include the TIM23 translocase responsible for the transfer of precursor proteins into the matrix and the MIA machinery required for the biogenesis of intermembrane space proteins. Dysfunctions of mitochondrial protein sorting pathways result in diminishing specific substrate proteins, followed by systemic pathology of the organelle and organismal death1-4. Cellular responses that are caused by accumulation of mitochondrial precursor proteins in the cytosol are largely unknown. Here we show a comprehensive picture of the changes in the cellular transcriptome and proteome in response to the stress associated with protein import dysfunction. We identify pathways that protect the cell against mitochondrial biogenesis defects by inhibiting protein synthesis and by activation of the proteasome, a major machine for cellular protein clearance. The proteasomal activity is modulated in proportion to the quantity of mislocalized mitochondrial precursor proteins in the cytosol. We propose that this type of unfolded protein response activated by mistargeting of proteins (UPRam) is beneficial for the cells. UPRam provides a means for buffering the consequences of physiological slowdown in mitochondrial protein import and for counteracting pathologies that are caused or contributed by mitochondrial dysfunction.

2015-07-31 | PXD001495 | Pride

The combination human 13 gene mutation Detection kit (reversible terminal termination sequencing) complements the clinical trial

Project description:Interventions: Gold Standard:Comparison methods :(1) comparison of similar kits;(2) Sequencing method;Index test:Human 13 gene mutation Combination Detection Kit (reversible terminal termination sequencing method) Primary outcome(s): Lung and gastrointestinal tumor genes Study Design: Sequential

| 2696826 | ecrin-mdr-crc

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