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Inter-organellar and systemic survival responses to impaired mitochondrial matrix protein import in skeletal muscle

ABSTRACT: Inter-organellar and systemic survival responses to impaired mitochondrial matrix protein import in skeletal muscle

PROVIDER: PRJNA815842 | ENA |

REPOSITORIES: ENA

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Inter-organellar and systemic survival responses to impaired mitochondrial matrix protein import in skeletal muscle

Project description:Mitochondrial functions are largely performed by proteins imported from cytosol. Impaired protein import in mitochondria affects the maintenance of intra-mitochondrial anabolic and energy metabolic pathways. It leads to cytosolic accumulation of mistargeted proteins and activation of cellular stress responses. To explore the communication between these mechanism in mammalian system, we targeted the co-chaperone of mitochondrial Hsp70, a GrpE Like protein 1 (Grpel1), in mice. We show that loss of protein import into mitochondrial matrix results in mitochondrial dysfunction, which triggers stress responses. The total shut down of mtHSP70 function by overall knockout of Grpel1 resulted in early embryonic lethality, and tamoxifen-induced skeletal muscle-specific knockout of Grpel1 caused rapid muscular atrophy. We show here, with transcriptomics analysis, that protein-import failure in mitochondria increased cellular proteotoxic stress due to mitochondrial dysfunction. As a control mechanism, it triggered adaptive stress responses, including unfolded protein responses and integrated stress responses. Metabolic profiling of skeletal muscle-specific knockout mice revealed amino acid and TCA cycle intermediates shuttle between serum and muscle.

2022-10-04 | GSE198540 | GEO

Inter-organellar and systemic responses to impaired mitochondrial matrix protein import in skeletal muscle.

Project description:Effective protein import from cytosol is critical for mitochondrial functions and metabolic regulation. We describe here the mammalian muscle-specific and systemic consequences to disrupted mitochondrial matrix protein import by targeted deletion of the mitochondrial HSP70 co-chaperone GRPEL1. Muscle-specific loss of GRPEL1 caused rapid muscle atrophy, accompanied by shut down of oxidative phosphorylation and mitochondrial fatty acid oxidation, and excessive triggering of proteotoxic stress responses. Transcriptome analysis identified new responders to mitochondrial protein import toxicity, such as the neurological disease-linked intermembrane space protein CHCHD10. Besides communication with ER and nucleus, we identified crosstalk of distressed mitochondria with peroxisomes, in particular the induction of peroxisomal Acyl-CoA oxidase 2 (ACOX2), which we propose as an ATF4-regulated peroxisomal marker of integrated stress response. Metabolic profiling indicated fatty acid enrichment in muscle, a shift in TCA cycle intermediates in serum and muscle, and dysregulated bile acids. Our results demonstrate the fundamental importance of GRPEL1 and provide a robust model for detecting mammalian inter-organellar and systemic responses to impaired mitochondrial matrix protein import and folding.

| S-EPMC9534917 | biostudies-literature

Inter-organellar communication by a mitochondrial tRNA regulates nuclear metabolic transcription

Project description:Inter-organellar communication by a mitochondrial tRNA regulates nuclear metabolic transcription

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Inter-organellar communication by a mitochondrial tRNA regulates nuclear metabolic transcription (RNA-Seq)

Project description:Inter-organellar communication by a mitochondrial tRNA regulates nuclear metabolic transcription (RNA-Seq)

| PRJNA879447 | ENA

Impaired fatty acid import and metabolism in macrophages restricts intracellular growth of Mycobacterium tuberculosis

Project description:Impaired fatty acid import and metabolism in macrophages restricts intracellular growth of Mycobacterium tuberculosis

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Inter-organellar communication by a mitochondrial tRNA regulates nuclear metabolic transcription (GRO-Seq and CUT&RUN)

Project description:Inter-organellar communication by a mitochondrial tRNA regulates nuclear metabolic transcription (GRO-Seq and CUT&RUN)

| PRJNA879446 | ENA

Impaired fatty acid import and metabolism in macrophages restricts intracellular growth of Mycobacterium tuberculosis

Project description:Mycobacterium tuberculosis (Mtb) infection of macrophages reprograms cellular lipid metabolism to promote the formation of cytosolic lipid droplets. While it is clearly known that intracellular Mtb utilize host derived fatty acids and cholesterol to fuel a majority of its biosynthetic demands, the role of macrophage lipid metabolism on the bacteria’s ability to access the intracellular lipid pool remains controversial. We have utilized a CRISPR genetic knockdown approach to, systematically and comprehensively, characterize the role of macrophage fatty acid metabolism on the intracellular growth of Mtb. Our analyzes demonstrate that knockdown of lipid import, sequestration and metabolism genes collectively impair the intracellular growth of Mtb in macrophages. We further demonstrate that modulating fatty acids homeostasis in macrophages impair Mtb replication by enhancing production of pro-inflammatory cytokines, restricting the bacteria access to nutrients and increasing oxidative stress in a manner which is surprisingly divergent. We also demonstrate that impaired macrophage lipid droplet biogenesis is restrictive to intracellular Mtb growth. However, increased induction of lipid droplet formation by downstream blockade of fatty acid oxidation does not rescue the impaired Mtb growth phenotypes. Our work provides a characterization of macrophage fatty acid homeostasis and how its modulation impacts Mtb intracellular growth.

2024-06-24 | GSE270571 | GEO

Kinetics of the Arabidopsis organellar and nuclear (post)transcriptomes under drought stress

Project description:We extended the investigation of nuclear transcript changes under drought to an overarching characterization of the post(transcriptome), including alternative splicing of nuclear transcripts, accumulation of organellar (chloroplast and mitochondrion) transcripts, editing and splicing of organellar transcripts, and furthermore, accumulation of transposable elements. To this end, long non-coding (lncRNA-Seq) instead of mRNA-Seq was applied, because the lncRNA-Seq workflow employs library preparation after ribosomal RNA depletion instead of library preparation of enriched mRNAs (mRNA-Seq).

2023-08-09 | GSE202931 | GEO

Control of the mitochondrial carrier import pathway by DYRK1A

Project description:Mitochondria require a complete and functional proteome to maintain a plethora of metabolic reactions in a cell. Changes in cellular demands depend on a rapid adaptation of the mitochondrial proteome. The translocase of the outer membrane TOM, constitutes the organellar entry gate that imports nearly all proteins as precursors from the cytosol. It is therefore an ideal target for cytosolic signalling pathways to regulate organellar protein influx. Here we identify the human mitochondrial import receptor TOM70 as a target of the cytosolic kinase DYRK1A. Phosphorylation of TOM70Ser91 by DYRK1A does not affect precursor binding but stimulates the interaction of the peripheral import receptor with the core TOM complex to enable increased precursor translocation. Thus TOM70Ser91 phosphorylation by DYRK1A provides a regulatory switch for the carrier import pathway in human mitochondria. DYRK1A has not been linked to mitochondria before. Regulation of protein import by DYRK1A provides an efficient mean to adapt the mitochondrial proteome to changing cellular needs and may also build a basis for the understanding of disease mechanisms caused by dysfunctional DYRK1A.

2021-05-31 | PXD019520 | Pride

Charting Organellar Importomes by Quantitative Mass Spectrometry -SAM50

Project description:Protein import into organelles is essential for all eukaryotes and facilitated by multi-protein translocation machineries. Analyzing whether a protein is transported into an organelle is largely restricted to single constituents. This renders knowledge about imported proteins incomplete, limiting our understanding of organellar biogenesis and function. Here, we introduce a method that enables to chart an organelle’s importome. Our method relies on inducible RNAi-mediated knockdown of an essential subunit of a translocase to impair import, metabolic labeling and quantitative mass spectrometry. To highlight its potential, we established the mitochondrial importome of Trypanosoma brucei, comprising 1,120 proteins including 331 new candidates. An exciting feature of this method is that it overcomes limitations in identifying proteins with dual or multiple locations. We demonstrate the specificity and versatility of this novel ImportOmics method by targeting import machineries in mitochondria and glycosomes demonstrating its high potential for globally studying protein import and inventories of organelles.

2017-06-14 | PXD004979 | Pride

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