Mitochondrial Proteostatic Stress Induces Aggrephagy to Triage Unimported Proteins
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ABSTRACT:
PROVIDER: PRJNA427882 | ENA |
REPOSITORIES: ENA
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Project description: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.
2018-12-29 | GSE108622 | GEO
Project description:Cytosolic Proteostatic Adaptation to Mitochondrial Stress Causes Progressive Muscle Wasting
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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
Project description:Proteostasis is essential for survival and particularly important for highly specialized post mitotic cells like neurons. Transient reduction of protein synthesis by protein kinase R–like endoplasmic reticulum (ER) kinase (PERK)-mediated phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) is a major proteostatic survival response during ER stress. Paradoxically, neurons are remarkably tolerant to PERK dysfunction, which suggests the existence of cell type-specific mechanisms that secure proteostatic stress resilience. We employed PERK-deficient neuron and astrocyte monocultures to investigate the mechanisms underlying neuron-specific ER stress resilience in the absence of PERK.
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Project description:Mitochondrial hypoxic stress induces RNA editing by APOBEC3G in lymphocytes
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Project description:Mitochondrial functions are essential for cell viability and rely on protein import into the organelle. Various disease and stress conditions can lead to mitochondrial import defects. We find that inhibition of mitochondrial import in budding yeast activates a surveillance mechanism, mitoCPR, that is aimed at ameliorating mitochondrial import and protecting mitochondria during import stress. mitoCPR induces expression of Cis1 which associates with the mitochondrial translocase to reduce the accumulation of mitochondrial precursor proteins at the organelle surface. Clearance of precursor proteins depends on the Cis1 interacting AAA+ ATPase Msp1 and the proteasome suggesting that Cis1 facilitates degradation of un-imported proteins at the mitochondrial surface.
2018-04-20 | GSE107784 | GEO
Project description:Protein recoding by RNA editing is required for normal health and evolutionary adaptation. However, de novo induction of RNA editing in response to environmental factors is an uncommon phenomenon. While APOBEC3A edits many mRNAs in monocytes/macrophages in response to hypoxia and interferons, the physiological significance of such editing is unclear. Here we show that the related APOBEC3G cytidine deaminase induces site-specific C-to-U RNA editing in natural killer (NK), CD8+ T cells and lymphoma cell lines upon cellular crowding and hypoxia. RNA seq analysis of hypoxic NK cells reveals C-to-U recoding mRNA editing in dozens of genes including multiple translational and ribosomal genes. APOBEC3G promotes Warburg-like metabolic remodeling and reduces proliferation of HuT78 T cells under similar conditions. Hypoxia-induced RNA editing by APOBEC3G can be mimicked by the inhibition of mitochondrial respiration, and occurs independently of HIF-1α. Thus, APOBEC3G induces mRNA editing in lymphocytes to promote adaptation to mitochondrial hypoxic stress.
2018-11-22 | GSE114519 | GEO
Project description:Fisetin induces autophagy in pancreatic cancer cells via endoplasmic reticulum stress- and mitochondrial stress-dependent pathways
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Project description:Organisms respond to mitochondrial stress through the upregulation of an array of protective genes, often perpetuating an early response to metabolic dysfunction across a lifetime. We find that mitochondrial stress causes widespread changes in chromatin structure through histone H3K9 di-methylation marks traditionally associated with gene silencing. Mitochondrial stress response activation requires the di-methylation of histone H3K9 through the activity of the histone methyltransferase met-2 and the nuclear co-factor lin-65. While globally the chromatin becomes silenced by these marks, remaining portions of the chromatin open up, at which point the binding of canonical stress responsive factors such as DVE-1 occurs. Thus, a metabolic stress response is established and propagated into adulthood of animals through specific epigenetic modifications that allow for selective gene expression and lifespan extension.
2016-05-03 | GSE78252 | GEO
Project description:Hyperaccurate mitochondrial translation increases cellular proteostatic capacity
| PRJEB17642 | ENA