About: Analysis of the Potential for N(4)-Hydroxycytidine To Inhibit Mitochondrial Replication and Function

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An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Analysis of the Potential for N(4)-Hydroxycytidine To Inhibit Mitochondrial Replication and Function
Creator	Kolykhalov, Alexander Lu, Gaofei Marlow, Joshua Moellering, Levi Bluemling, Gregory Natchus, Michael Painter, George Guthrie, David Mitchell, Deborah Sticher, Zachary
Source	PMC
abstract	N(4)-Hydroxycytidine (NHC) is an antiviral ribonucleoside analog that acts as a competitive alternative substrate for virally encoded RNA-dependent RNA polymerases. It exhibits measurable levels of cytotoxicity, with 50% cytotoxic concentration values ranging from 7.5 μM in CEM cells and up to >100 μM in other cell lines. The mitochondrial DNA-dependent RNA polymerase (POLRMT) has been shown to incorporate some nucleotide analogs into mitochondrial RNAs, resulting in substantial mitochondrial toxicity. NHC was tested in multiple assays intended to determine its potential to cause mitochondrial toxicity. NHC showed similar cytotoxicity in HepG2 cells incubated in a glucose-free and glucose-containing media, suggesting that NHC does not impair mitochondrial function in this cell line based on the Crabtree effect. We demonstrate that the 5′-triphosphate of NHC can be used by POLRMT for incorporation into nascent RNA chain but does not cause immediate chain termination. In PC-3 cells treated with NHC, the 50% inhibitory concentrations of mitochondrial protein expression inhibition were 2.7-fold lower than those for nuclear-encoded protein expression, but this effect did not result in selective mitochondrial toxicity. A 14-day incubation of HepG2 cells with NHC had no effect on mitochondrial DNA copy number or extracellular lactate levels. In CEM cells treated with NHC at 10 μM, a slight decrease (by ∼20%) in mitochondrial DNA copy number and a corresponding slight increase in extracellular lactate levels were detected, but these effects were not enhanced by an increase in NHC treatment concentration. In summary, the results indicate that mitochondrial impairment by NHC is not the main contributor to the compound’s observed cytotoxicity in these cell lines.
has issue date	2020-01-27(xsd:dateTime)
bibo:doi	10.1128/aac.01719-19
bibo:pmid	31767721
has license	cc-by
sha1sum (hex)	55f72abf2de5e0b70b27e9ed512b9e456407b680
schema:url	https://doi.org/10.1128/aac.01719-19
resource representing a document's title	Analysis of the Potential for N(4)-Hydroxycytidine To Inhibit Mitochondrial Replication and Function
has PubMed Central identifier	PMC6985706
has PubMed identifier	31767721
schema:publication	Antimicrob Agents Chemother
resource representing a document's body	covid:55f72abf2de5e0b70b27e9ed512b9e456407b680#body_text
is schema:about of	named entity 'triphosphate' named entity 'mitochondrial toxicity' named entity 'observed' named entity 'intended' named entity 'competitive' named entity 'cells' named entity 'NHC' named entity 'mitochondrial toxicity' named entity 'slight' named entity 'LACTATE LEVELS' named entity 'CELL LINE' named entity 'EXTRACELLULAR' named entity 'INCUBATION' named entity '7.5' named entity 'EXHIBITS' named entity 'CAUSE' named entity 'DETECTED' named entity 'DEPENDENT' named entity 'CONTRIBUTOR' named entity 'SIMILAR' named entity 'DAY' named entity 'DECREASE' named entity 'MITOCHONDRIAL TOXICITY' named entity 'POTENTIAL' named entity '27S' named entity 'SLIGHT' named entity 'DOES NOT' named entity 'IMPAIRMENT' named entity 'INHIBITION' named entity 'MEDIA' named entity 'FOLD' named entity 'MITOCHONDRIAL' named entity 'MITOCHONDRIAL PROTEIN' named entity 'RNA' named entity 'CONCENTRATION' named entity 'IMPAIR' named entity 'DETERMINE' named entity 'TRIPHOSPHATE' named entity 'ALTERNATIVE' named entity 'SELECTIVE' named entity 'SUBSTRATE' named entity 'LEVELS' named entity 'MITOCHONDRIAL DNA' named entity 'ACTS' named entity 'AT 10' named entity 'CHAIN TERMINATION' named entity 'NUCLEOTIDE' named entity 'CELLS' named entity 'ENCODED' named entity 'POLYMERASES' named entity 'RESULT' named entity 'HEPG2' named entity '50%' named entity 'RIBONUCLEOSIDE' named entity 'DID' named entity 'MEASURABLE' named entity 'THESE' named entity 'IMMEDIATE' named entity 'MAIN' named entity 'SUMMARY' named entity 'OBSERVED' named entity 'DNA-DEPENDENT RNA POLYMERASE' named entity 'VALUES' named entity 'REPLICATION' named entity 'POTENTIAL' named entity 'TO INHIBIT' named entity 'COMPETITIVE' named entity 'GLUCOSE' named entity 'POLRMT' named entity 'MITOCHONDRIAL FUNCTION' named entity 'COMPOUND' named entity 'FUNCTION'

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