Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE198540 | GEO | 2022/10/04

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Mitochondrial protein import stress augments alpha-synuclein aggregation and neurodegeneration independent of bioenergetics

Project description:Several genetic and environmental risk factors for Parkinson’s disease have been identified that converge on mitochondria as central elements in the disease process. However, the mechanisms by which mitochondrial dysfunction contributes to neurodegeneration remain incompletely understood. Non-bioenergetic pathways of the mitochondria are increasingly appreciated, but confounding bioenergetic defects are a major barrier to experimental validation. Here, we describe a novel bioenergetics-independent mechanism by which mild mitochondrial protein import stress augments neurodegeneration. We induced this mitochondrial protein import stress in an established mouse model of Parkinson’s disease expressing the A53T mutated form of human alpha-synuclein (SNCA). Mice with import stress in addition to the A53T mutation demonstrated increased size of SNCA aggregates, co-aggregation of mitochondrial preproteins with SNCA protein, worsened neurodegeneration and changes in gene expression, as determined by whole-transcriptome RNA-sequencing analysis of the forebrain (striatum), cerebellum, spinal cord, as well as heart and skeletal muscle.

2023-10-08 | GSE236975 | GEO

mitoCPR - a surveillance pathway that protects mitochondria in response to mitochondrial import stress [yeast]

Project description:Mitochondrial functions are essential for cell viability and rely on protein import into the organelle. Physiological perturbations and disease conditions can lead to mitochondrial import defect. We find that in budding yeast, mitochondrial import defects result in activation of a surveillance mechanism, which we termed mitoCPR. The mitoCPR is aimed at ameliorating mitochondrial import and protecting mitochondria during import stress. This is mediated by the mitoCPR effector, Cis1, which associates with mitochondria to reduce the accumulation of mitochondrial preproteins at the organelle's surface. Clearance of preproteins depends on the AAA-ATPase Msp1 and the proteasome, suggesting that Cis1 facilitates the degradation of unimported proteins that accumulate at the mitochondrial surface. We further show that mitoCPR is critical for maintaining mitochondrial functions during mitochondrial import stress and provide evidence that it is an ancient, conserved mitochondrial protection mechanism.

2019-03-16 | GSE96727 | GEO

mitoCPR - a surveillance pathway that protects mitochondria in response to mitochondrial import stress [human]

2019-03-16 | GSE96726 | GEO

mitoCPR - a surveillance pathway that protects mitochondria in response to mitochondrial import stress

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

RNAseq analysis of skeletal muscle transcriptomes from wild-type and LONP1 skeletal muscle specific knockout (LONP1-MKO) mice

Project description:Mitochondria serve diverse functions and are essential organelles that require continuous surveillance to maintaintheir integrity and function. LONP1 is an evolutionarily conservedserine peptidase that safeguards mitochondrial protein quality from yeast to human.To investigatethe physiological role of LONP1-mediated mitochondrial quality-control in skeletal musclein vivo, we generated skeletal muscle-specificLonp1-knockout mice (referred to as LONP1 MKO). We performedtranscriptome analysis by whole-genome gene expression profiling experiments in gastrocnemius (GC) muscle from both wild-type (WT) and LONP1-MKO mice. Knockout of LONP1 in skeletal muscle resulted in deregulation of 457 genes in 2-week-old mice and of 1922 genes in 6-week-old mice. Gene ontology analysis revealed that LONP1 deficiency triggers unfolded protein response (UPR) in skeletal muscle.Moreover, GSEA analysis of transcriptomic datain 6-week-old micefurther revealed that genes deregulated by LONP1 deficiency were significantly enriched during aging.Together, the transcriptional profiling results suggest a critical role of LONP1 in regulating skeletal muscle metabolism and health.

2022-01-05 | GSE166071 | GEO

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

Profiling of mRNA localization of nuclear-encoded mitochondrial proteins in zebrafish.

Project description:Current evidence suggests that nuclear-encoded mitochondrial proteins can be locally translated at the mitochondrial surface and co-translationally or post-translationally imported into mitochondria. mRNA localization on the mitochondrial membrane, a prerequisite for localized translation, remains uncharacterized in higher eukaryotic organisms. We employed fractionation-sequencing to profile mitochondria-associated mRNAs in zebrafish larvae. Our transcriptome-wide analysis reveals the localization of mRNAs of only 12% of the nuclear-encoded mitochondrial proteins to the mitochondrial surface, which suggests that post-translational import is the dominant mode of protein import to mitochondria. Additionally, the mRNAs which were localized to the mitochondrial membrane consisted mostly of those encoding proteins involved in mitochondrial dynamics, suggesting their site-specific translation. Finally, we show that the loss of function of the MIA pathway responsible for the post-translational import of a subclass of mitochondrial proteins, triggers mitochondrial localization of mRNAs encoding proteins that are imported to mitochondria via other pathways. Thus, our study suggests that mRNA targeting and localized translation could be relevant in higher eukaryotes to combat stress conditions affecting mitochondrial biogenesis in general.

2023-10-28 | GSE160355 | GEO

RNAseq skeletal muscle FUNDC1-mKO mice

Project description:This experiment was conducted to identify mRNA transcripts alteration in muscle from skeletal muscle-sepcific Fundc1-knockout mice. The following abstract from the submitted manuscript describes the major findings of this work. Mitophagy directs muscle-adipose crosstalk to alleviate dietary obesity. Tingting Fu, Zhisheng Xu, Lin Liu, Qiqi Guo, Hao Wu, Xijun Liang, Danxia Zhou, Liwei Xiao, Lei Liu, Yong Liu, Min-Sheng Zhu, Quan Chen and Zhenji Gan. The quality of mitochondria in skeletal muscle is essential for maintaining metabolic homeostasis during adaptive stress responses. However, the precise control mechanism of muscle mitochondrial quality and its physiological impacts remain unclear. Here, we demonstrate that FUNDC1, a mediator of mitophagy, plays a critical role in controlling muscle mitochondrial quality as well as metabolic homeostasis. Skeletal muscle-specific ablation of FUNDC1 in mice resulted in LC3-mediated mitophagy defect, leading to impaired mitochondrial energetics. This caused decreased muscle fat utilization and endurance capacity during exercise. Interestingly, mice lacking muscle FUNDC1 were protected against high-fat diet-induced obesity with improved systemic insulin sensitivity and glucose tolerance despite reduced muscle mitochondrial energetics. Mechanistically, FUNDC1 deficiency elicited a retrograde response in muscle that upregulated FGF21 expression, thereby promoting the thermogenic remodeling of adipose tissue. Thus, these findings reveal a pivotal role of FUNDC1-dependent mitochondrial quality-control in mediating the muscle-adipose dialogue to regulate systemic metabolism.

2018-05-01 | GSE99803 | GEO

Expression data from 2-amino acetophenone (2-AA) treated mouse Skeletal muscle

Project description:Metabolic responses begin promptly upon the initiation of infection, and progress as a series of coordinated events. Mitochondria may play a key role in the development of insulin resistance. Reduced energy production and mitochondrial dysfunctional may further favor infection, and be an important step in the establishment of chronic and persistent infections. We have used mouse skeletal muscle transcriptome data which have led to the hypothesis that 2-AA causes harm to the host by triggering mitochondrial dysfunction in skeletal muscle. The gastrocnemius muscles were isolated from control and 4days 2-AA treated mouse for RNA extraction and hybridization on Affymetrix microarrays.

2013-01-28 | E-GEOD-43779 | biostudies-arrayexpress

Regulation of translation under mitoprotein-induced stress in Saccharomyces cerevisiae

Project description:Proteotoxic stress triggers adaptive cellular responses, including changes in gene expression on the levels of transcription and translation. In this study, we analyzed the translational response of yeast cells to impaired protein import into mitochondria, a condition under which mitochondrial precursor proteins accumulate in the cytosol and impose proteotoxic stress. We analyzed changes in translational efficiency as well as more subtle changes in the distribution of ribosomes along transcripts, with a special focus on translation initiation sites.

2021-12-14 | GSE172017 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data