Methods to Study the Mitochondrial Unfolded Protein Response (UPRmt) in Caenorhabditis elegans

Haeussler, Simon; Conradt, Barbara

doi:10.1007/978-1-0716-1732-8_16

Cited by 6 publications

(2 citation statements)

References 49 publications

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“…For example, P. aeruginosa produces toxins that target the mitochondrial unfolded protein response (UPR MT ), 72 a transcriptional pathway that ensures proper protein folding and clearance. 73 As such, when the UPR MT is overwhelmed or disrupted, proteotoxicity can occur, leading to accelerated protein aggregation. 74 Our previous work demonstrated that P. aeruginosa and E. coli can also disrupt host proteostasis through the production of bacteria-derived protein aggregates.…”

Section: Proteotoxic Bacteria Enhance the Aggregation And Toxicity Of...mentioning

confidence: 99%

Identification of proteotoxic and proteoprotective bacteria that non-specifically affect proteins associated with neurodegenerative diseases

Walker,

Bhargava,

Bucher

et al. 2023

Preprint

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Neurodegenerative protein conformational diseases (PCDs), such as Alzheimer's, Parkinson's, and Huntington's, are a leading cause of death and disability worldwide and have no known cures or effective treatments. Emerging evidence suggests a role for the gut microbiota in the pathogenesis of neurodegenerative PCDs; however, the influence of specific bacteria on the culprit proteins associated with each of these diseases remains elusive, primarily due to the complexity of the microbiota. In the present study, we employed a single-strain screening approach to identify human bacterial isolates that enhance or suppress the aggregation of culprit proteins and the associated toxicity in Caenorhabditis elegans expressing Abeta1-42, alpha-synuclein, and polyglutamine tracts. Here, we reveal the first comprehensive analysis of the human microbiome for its effect on proteins associated with neurodegenerative diseases. Our results suggest that bacteria affect the aggregation of metastable proteins by modulating host proteostasis rather than selectively targeting specific disease-associated proteins. These results reveal bacteria that potentially influence the pathogenesis of PCDs and open new promising prevention and treatment opportunities by altering the abundance of beneficial and detrimental microbes.

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Section: Proteotoxic Bacteria Enhance the Aggregation And Toxicity Of...mentioning

confidence: 99%

Identification of proteotoxic and proteoprotective bacteria that non-specifically affect proteins associated with neurodegenerative diseases

Walker,

Bhargava,

Bucher

et al. 2023

Preprint

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“…[116] Contrary to the UPR mt induced in nematodes and flies and the cytosolic response mitochondrial stress in yeast, the heat-shock proteins (i.e., cytosolic HSP70 or mitochondrial HSPD1) are not a target of the DELE1-HRI pathway. [114,115,117] Specifically, it was shown that blockade of the OMA1-DELE1-HRI pathway upon mitochondrial stress blunts the expression of ATF4 and CHOP targets, whereas it leads to activation of heat shock protein expression. [114,115] The latter suggests that the transcriptional outcome upon mitochondrial protein import perturbations may vary depending on the trigger, and the molecular players involved.…”

Section: Mitochondrial Unfolded Protein Response (Uprmt)mentioning

confidence: 99%

Mitochondrial protein import machinery conveys stress signals to the cytosol and beyond

2023

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Mitochondria hold diverse and pivotal roles in fundamental processes that govern cell survival, differentiation, and death, in addition to organismal growth, maintenance, and aging. The mitochondrial protein import system is a major contributor to mitochondrial biogenesis and lies at the crossroads between mitochondrial and cellular homeostasis. Recent findings highlight the mitochondrial protein import system as a signaling hub, receiving inputs from other cellular compartments and adjusting its function accordingly. Impairment of protein import, in a physiological, or disease context, elicits adaptive responses inside and outside mitochondria. In this review, we discuss recent developments, relevant to the mechanisms of mitochondrial protein import regulation, with a particular focus on quality control, proteostatic and metabolic cellular responses, triggered upon impairment of mitochondrial protein import. K E Y W O R D Smetabolism, mitochondrial protein import, mitochondrial unfolded protein response, mitophagy, proteostasis Recent findings from system biology studies in whole cells (in vivo) have highlighted the mitochondrial protein import system as a critical

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Perillaldehyde alleviates polyQ‐induced neurodegeneration through the induction of autophagy and mitochondrial UPR in Caenorhabditis elegans

Fang,

Liu,

Gao

et al. 2024

BioFactors

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Huntington's disease (HD) is a fatal neurodegenerative disease associated with autophagy disorder and mitochondrial dysfunction. Here, we identified therapeutic potential of perillaldehyde (PAE), a monoterpene compound obtained from Perilla frutescens (L.) Britt., in the Caenorhabditis elegans (C. elegans) model of HD, which included lifespan extension, healthspan improvement, decrease in polyglutamine (polyQ) aggregation, and preservation of mitochondrial network. Further analyses indicated that PAE was able to induce autophagy and mitochondrial unfolded protein reaction (UPRmt) activation and positively regulated expression of associated genes. In lgg‐1 RNAi C. elegans or C. elegans with UPRmt‐related genes knockdown, the effects of PAE treatment on polyQ aggregation or rescue polyQ‐induced toxicity were attenuated, suggesting that its neuroprotective activity depended on autophagy and UPRmt. Moreover, we found that pharmacological and genetic activation of UPRmt generally protected C. elegans from polyQ‐induced cytotoxicity. Finally, PAE promoted serotonin synthesis by upregulating expression of TPH‐1, and serotonin synthesis and neurosecretion were required for PAE‐mediated UPRmt activation and its neuroprotective activity. In conclusion, PAE is a potential therapy for polyQ‐related diseases including HD, which is dependent on autophagy and cell‐non‐autonomous UPRmt activation.

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Methods to Study the Mitochondrial Unfolded Protein Response (UPRmt) in Caenorhabditis elegans

Cited by 6 publications

References 49 publications

Identification of proteotoxic and proteoprotective bacteria that non-specifically affect proteins associated with neurodegenerative diseases

Identification of proteotoxic and proteoprotective bacteria that non-specifically affect proteins associated with neurodegenerative diseases

Mitochondrial protein import machinery conveys stress signals to the cytosol and beyond

Perillaldehyde alleviates polyQ‐induced neurodegeneration through the induction of autophagy and mitochondrial UPR in Caenorhabditis elegans

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