Deficiencies in mitochondrial dynamics sensitize Caenorhabditis elegans to arsenite and other mitochondrial toxicants by reducing mitochondrial adaptability
| Autor: | Laura L. Maurer, Latasha L. Smith, Tewodros R. Godebo, Tess C. Leuthner, Anthony L. Luz, Joel N. Meyer |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Dynamins Genotype Arsenites Ubiquitin-Protein Ligases Mitochondrial Degradation MFN2 PINK1 Biology Mitochondrion Protein Serine-Threonine Kinases Toxicology Mitochondrial Dynamics Article GTP Phosphohydrolases 03 medical and health sciences 0302 clinical medicine medicine Autophagy MFN1 Animals Caenorhabditis elegans Caenorhabditis elegans Proteins Dose-Response Relationship Drug Mitophagy medicine.disease Sodium Compounds Mitochondria Mitochondrial toxicity 030104 developmental biology Phenotype mitochondrial fusion Biochemistry Larva Mitochondrial fission Gene-Environment Interaction 030217 neurology & neurosurgery |
| Zdroj: | Toxicology. 387 |
| ISSN: | 1879-3185 |
| Popis: | Mitochondrial fission, fusion, and mitophagy are interlinked processes that regulate mitochondrial shape, number, and size, as well as metabolic activity and stress response. The fundamental importance of these processes is evident in the fact that mutations in fission (DRP1), fusion (MFN2, OPA1), and mitophagy (PINK1, PARK2) genes can cause human disease (collectively >1/10,000). Interestingly, however, the age of onset and severity of clinical manifestations varies greatly between patients with these diseases (even those harboring identical mutations), suggesting a role for environmental factors in the development and progression of certain mitochondrial diseases. Using the model organism Caenorhabditis elegans, we screened ten mitochondrial toxicants (2, 4-dinitrophenol, acetaldehyde, acrolein, aflatoxin B1, arsenite, cadmium, cisplatin, doxycycline, paraquat, rotenone) for increased or decreased toxicity in fusion (fzo-1, eat-3)-, fission (drp-1)-, and mitophagy (pdr-1, pink-1)-deficient nematodes using a larval growth assay. In general, fusion-deficient nematodes were the most sensitive to toxicants, including aflatoxin B1, arsenite, cisplatin, paraquat, and rotenone. Because arsenite was particularly potent in fission- and fusion-deficient nematodes, and hundreds of millions of people are chronically exposed to arsenic, we investigated the effects of these genetic deficiencies on arsenic toxicity in more depth. We found that deficiencies in fission and fusion sensitized nematodes to arsenite-induced lethality throughout aging. Furthermore, low-dose arsenite, which acted in a "mitohormetic" fashion by increasing mitochondrial function (in particular, basal and maximal oxygen consumption) in wild-type nematodes by a wide range of measures, exacerbated mitochondrial dysfunction in fusion-deficient nematodes. Analysis of multiple mechanistic changes suggested that disruption of pyruvate metabolism and Krebs cycle activity underlie the observed arsenite-induced mitochondrial deficits, and these disruptions are exacerbated in the absence of mitochondrial fusion. This research demonstrates the importance of mitochondrial dynamics in limiting arsenite toxicity by permitting mitochondrial adaptability. It also suggests that individuals suffering from deficiencies in mitodynamic processes may be more susceptible to the mitochondrial toxicity of arsenic and other toxicants. |
| Databáze: | OpenAIRE |
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