Maintenance of Mitochondrial DNA by the <i>Caenorhabditis elegans</i> ATR Checkpoint Protein ATL-1

Mori, Chihiro; Takanami, Takako; Higashitani, Akihiro

doi:10.1534/genetics.108.090704

Cited by 11 publications

(7 citation statements)

References 35 publications

(54 reference statements)

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“…Properties that we examined included mitochondrial DNA (mtDNA) content, nuclear-encoded ETC transcript abundance, mitochondrial morphology and whole-worm oxygen consumption. Our findings can be summarized as follows: relative to wild type worms, mtDNA copy number is halved in atl-1(tm853) mutants, consistent with an earlier report 57 . mtDNA content was also halved in atl-1(tm853); atm-1(gk186) double mutants (Fig.…”

Section: Resultssupporting

confidence: 92%

Inhibition of ATR Reverses a Mitochondrial Respiratory Insufficiency

Borror¹,

Girotti²,

Kar³

et al. 2019

Preprint

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2Diseases that affect the mitochondrial electron transport chain (ETC) often manifest as threshold effect 2 3 disorders, meaning patients only become symptomatic once a certain level of ETC dysfunction is 2 4 reached. Multiple processes work to control proximity to the critical ETC threshold and as a 2 5 consequence there can be significant variability in disease presentation among patients. Identification 2 6 of such control processes remains an ongoing goal. Checkpoint signaling comprises a collection of alert 2 7 mechanisms activated in cells in response to nuclear DNA damage. Well-defined hierarchies of 2 8 proteins are involved in both sensing and signaling DNA damage, with ATM (ataxia telangiectasia 2 9 mutated) and ATR (ATM and Rad3-related) acting as pivotal signaling kinases. In the nematode 3 0 C. elegans, severe reduction of mitochondrial ETC activity shortens life, as in humans, but mild 3 1 2 reduction extends life as a consequence of survival strategies that are invoked under these 3 2 circumstances. Here we show that removal of ATL-1, the worm ortholog of ATR, unexpectedly lessens 3 3 the severity of ETC dysfunction, but removal of ATM does not. Multiple genetic and biochemical tests 3 4show no evidence for increased mutation or DNA breakage in animals exposed to ETC disruption. 5Instead, we find that reduced ETC function alters nucleotide ratios within both the ribo-and deoxyribo-3 6 nucleotide pools, and causes stalling of RNA polymerase, which is also known to activate 3 7 ATR. Unexpectedly, atl-1 mutants confronted with mitochondrial ETC disruption maintain normal levels 3 8 of oxygen consumption and have an increased abundance of translating ribosomes. This suggests 3 9 checkpoint signaling by ATL-1 normally dampens cytoplasmic translation. Taken together, our data 4 0 suggests a model whereby ETC insufficiency in C. elegans results in nucleotide imbalances leading to 4 1 stalling of RNA polymerase, activation of ATL-1, dampening of global translation and magnification of 4 2 ETC dysfunction. Loss of ATL-1 effectively reverses the severity of ETC disruption so that animals 4 3 become phenotypically closer to wild type.

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Section: Resultssupporting

confidence: 92%

Inhibition of ATR Reverses a Mitochondrial Respiratory Insufficiency

Borror¹,

Girotti²,

Kar³

et al. 2019

Preprint

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“…SJ4100: zcIs13[Phsp-6:GFP] V (Benedetti et al 2006). DW101: atl-1(tm853) V / nT1[unc(n754) let (qIs50)] (IV, V) (Mori et al 2008). TJ1: cep-1(gk138) I (Arum and Johnson 2007).…”

Section: Methodsmentioning

confidence: 99%

Stress-Induced Sleep After Exposure to Ultraviolet Light Is Promoted by p53 inCaenorhabditis elegans

2017

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Stress-induced sleep (SIS) in is important for restoration of cellular homeostasis and is a useful model to study the function and regulation of sleep. SIS is triggered when epidermal growth factor (EGF) activates the ALA neuron, which then releases neuropeptides to promote sleep. To further understand this behavior, we established a new model of SIS using irradiation by ultraviolet C (UVC) light. While UVC irradiation requires ALA signaling and leads to a sleep state similar to that induced by heat and other stressors, it does not induce the proteostatic stress seen with heat exposure. Based on the known genotoxic effects of UVC irradiation, we tested two genes, and , which encode proteins that act in the DNA damage response pathway. Loss-of-function mutants of had no defect in UVC-induced SIS but a partial loss-of-function mutant of ,, had decreased movement quiescence following UVC irradiation. Germline ablation experiments and tissue-specific RNA interference experiments showed that is required somatically in neurons for its effect on SIS. The() mutant suppressed body movement quiescence controlled by EGF, indicating that CEP-1 acts downstream or in parallel to ALA activation to promote quiescence in response to ultraviolet light.

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“…Animal models, such as Danio rerio (zebra fish) [234], Drosophila melanogaster (fruit fly) [235] and Caenorhabditis elegans (round worm) [236], develop rather quickly and the model can be manipulated by directly adding compounds to the food, medium or water, or irradiating their culture dish. Because the evolutionary distance to humans is larger than for mice, some of these organisms do not contain all the organs affected in humans [237].…”

Section: Mitochondrial Animal Modelsmentioning

confidence: 99%

How do changes in the mtDNA and mitochondrial dysfunction influence cancer and cancer therapy? Challenges, opportunities and models

Gisbergen

Voets

Starmans

et al. 2015

Mutation Research/Reviews in Mutation Research

165

151

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Several mutations in nuclear genes encoding for mitochondrial components have been associated with an increased cancer risk or are even causative, e.g. succinate dehydrogenase (SDHB, SDHC and SDHD genes) and iso-citrate dehydrogenase (IDH1 and IDH2 genes). Recently, studies have suggested an eminent role for mitochondrial DNA (mtDNA) mutations in the development of a wide variety of cancers. Various studies associated mtDNA abnormalities, including mutations, deletions, inversions and copy number alterations, with mitochondrial dysfunction. This might, explain the hampered cellular bioenergetics in many cancer cell types. Germline (e.g. m.10398A>G; m.6253T>C) and somatic mtDNA mutations as well as differences in mtDNA copy number seem to be associated with cancer risk. It seems that mtDNA can contribute as driver or as complementary gene mutation according to the multiple-hit model. This can enhance the mutagenic/clonogenic potential of the cell as observed for m.8993T>G or influences the metastatic potential in later stages of cancer progression. Alternatively, other mtDNA variations will be innocent passenger mutations in a tumor and therefore do not contribute to the tumorigenic or metastatic potential. In this review, we discuss how reported mtDNA variations interfere with cancer treatment and what implications this has on current successful pharmaceutical interventions. Mutations in MT-ND4 and mtDNA depletion have been reported to be involved in cisplatin resistance. Pharmaceutical impairment of OXPHOS by metformin can increase the efficiency of radiotherapy. To study mitochondrial dysfunction in cancer, different cellular models (like ρ(0) cells or cybrids), in vivo murine models (xenografts and specific mtDNA mouse models in combination with a spontaneous cancer mouse model) and small animal models (e.g. Danio rerio) could be potentially interesting to use. For future research, we foresee that unraveling mtDNA variations can contribute to personalized therapy for specific cancer types and improve the outcome of the disease.

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Maintenance of Mitochondrial DNA by the Caenorhabditis elegans ATR Checkpoint Protein ATL-1

Cited by 11 publications

References 35 publications

Inhibition of ATR Reverses a Mitochondrial Respiratory Insufficiency

Inhibition of ATR Reverses a Mitochondrial Respiratory Insufficiency

Stress-Induced Sleep After Exposure to Ultraviolet Light Is Promoted by p53 inCaenorhabditis elegans

How do changes in the mtDNA and mitochondrial dysfunction influence cancer and cancer therapy? Challenges, opportunities and models

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