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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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			Action	DRS
	SRR18318459_1.fastq.gz	Fastqsanger.gz
	SRR18318459_2.fastq.gz	Fastqsanger.gz
	SRR18318460_1.fastq.gz	Fastqsanger.gz
	SRR18318460_2.fastq.gz	Fastqsanger.gz
	SRR18318461_1.fastq.gz	Fastqsanger.gz

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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.

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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.

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

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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.

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