Mitochondrial Dysfunction Confers Resistance to Multiple Drugs in<i>Caenorhabditis elegans</i>

Zubovych, Iryna O.; Straud, Sarah; Roth, Michael G.

doi:10.1091/mbc.e09-08-0673

Cited by 49 publications

(50 citation statements)

References 45 publications

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“…Har-1 was originally identified from a C. elegans screen to detect mutants that survive in the presence of the antimitotic drug hemiasterlin, in which the har-1 G73E mutant was identified22. However, unlike the har-1 G73E mutant that exhibits a normal lifespan, har-1 −/− C. elegans observed in this study were short-lived.…”

Section: Discussionmentioning

confidence: 91%

Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity

et al. 2017

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Although multiple CHCHD10 mutations are associated with the spectrum of familial and sporadic frontotemporal dementia–amyotrophic lateral sclerosis (FTD–ALS) diseases, neither the normal function of endogenous CHCHD10 nor its role in the pathological milieu (that is, TDP-43 pathology) of FTD/ALS have been investigated. In this study, we made a series of observations utilizing Caenorhabditis elegans models, mammalian cell lines, primary neurons and mouse brains, demonstrating that CHCHD10 normally exerts a protective role in mitochondrial and synaptic integrity as well as in the retention of nuclear TDP-43, whereas FTD/ALS-associated mutations (R15L and S59L) exhibit loss of function phenotypes in C. elegans genetic complementation assays and dominant negative activities in mammalian systems, resulting in mitochondrial/synaptic damage and cytoplasmic TDP-43 accumulation. As such, our results provide a pathological link between CHCHD10-associated mitochondrial/synaptic dysfunction and cytoplasmic TDP-43 inclusions.

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Section: Discussionmentioning

confidence: 91%

Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity

et al. 2017

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“…FCCP is a proton ionophore, indicating that it is able to transport hydrogen ions across membranes. FCCP is therefore an uncoupling agent, since it disrupts ATP synthesis by transporting hydrogen ions across the inner mitochondrial membrane instead of the proton channel of the ATP synthase (complex V)66. Consequently, administration of FCCP results in the collapse of the mitochondrial membrane potential, thereby inducing a rapid increase in the consumption of energy and oxygen without the generation of ATP.…”

Section: Experimental Designmentioning

confidence: 99%

A screening-based platform for the assessment of cellular respiration in Caenorhabditis elegans

et al. 2016

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Mitochondrial dysfunction is at the core of many diseases, ranging from inherited metabolic diseases to common conditions that are associated with ageing. While associations between ageing and mitochondrial function have been identified using mammalian models, much of the mechanistic insight has emerged from C. elegans. Mitochondrial respiration is recognized as an indicator of mitochondrial health. Seahorse XF96 respirometers are the state-of-the-art platform to assess respiration in cells, and we adapted the technique for applications involving C. elegans. Here, we provide a detailed protocol to optimise and measure respiration in C. elegans with the XF96 respirometer, including the interpretation of parameters and results. The protocol takes ~2 days to complete, excluding time spent culturing C. elegans, and includes (i) the preparation of C. elegans samples, (ii) selection and loading of compounds to be injected, (iii) preparing and executing a run with the XF96 respirometer, and (iv) post-experimental data-analysis, including normalization. In addition, we compare our XF96 application with other existing techniques, including the 8-well Seahorse XFp. The main benefits of the XF96 include the limited number of worms required and high-throughput capacity due to 96-well format.

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“…This is most apparent in cyc-1 , in which 22 CYP, 23 UGT, and 9 GST genes are transcriptionally activated [132]. Additionally, mitochondrial mutants are resistant to diverse toxins, suggesting that the up-regulation of detoxification pathways in a mitochondrial mutant activates a general detoxification of toxins [133]. This, too, may contribute to lifespan extension following disruption of mitochondrial function.…”

Section: Daf-16-independent Cytoprotective Pathways To Lifespan Extenmentioning

confidence: 99%

A cytoprotective perspective on longevity regulation

Shore

Ruvkun

2013

Trends in Cell Biology

126

131

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There are many mechanisms of lifespan extension, including the disruption of insulin/IGF-1 signaling, metabolism, translation, or feeding. Despite the disparate functions of these pathways, inhibition of each induces responses that buffer stress and damage. Here, emphasizing data from genetic analyses in C. elegans, we explore the effectors and upstream regulatory components of numerous cytoprotective mechanisms activated as major elements of longevity programs, including detoxification, innate immunity, proteostasis, and oxidative stress response. We show that their induction underpins longevity extension across functionally diverse triggers and across species. Intertwined with the evolution of longevity, cytoprotective pathways are coupled to the surveillance of core cellular components, with important implications in normal and aberrant responses to drugs, chemicals, and pathogens.

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Mitochondrial Dysfunction Confers Resistance to Multiple Drugs inCaenorhabditis elegans

Cited by 49 publications

References 45 publications

Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity

Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity

A screening-based platform for the assessment of cellular respiration in Caenorhabditis elegans

A cytoprotective perspective on longevity regulation

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