RRC ID 51411
Author Luz AL, Godebo TR, Smith LL, Leuthner TC, Maurer LL, Meyer JN.
Title Deficiencies in mitochondrial dynamics sensitize Caenorhabditis elegans to arsenite and other mitochondrial toxicants by reducing mitochondrial adaptability.
Journal Toxicology
Abstract 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.
Volume 387
Pages 81-94
Published 2017-7-15
DOI 10.1016/j.tox.2017.05.018
PII S0300-483X(17)30165-8
PMID 28602540
PMC PMC5535741
MeSH Animals Arsenites / toxicity* Autophagy / drug effects Caenorhabditis elegans / drug effects* Caenorhabditis elegans / embryology Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Dose-Response Relationship, Drug Dynamins / genetics Dynamins / metabolism GTP Phosphohydrolases / genetics GTP Phosphohydrolases / metabolism Gene-Environment Interaction Genotype Larva / drug effects Larva / metabolism Mitochondria / drug effects* Mitochondria / metabolism Mitochondrial Dynamics / drug effects* Mitophagy / drug effects Phenotype Protein Serine-Threonine Kinases / genetics Protein Serine-Threonine Kinases / metabolism Sodium Compounds / toxicity* Ubiquitin-Protein Ligases / genetics Ubiquitin-Protein Ligases / metabolism
IF 4.099
Times Cited 21
C.elegans tm1108 tm1133 tm1779