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AMPK Activation prevents and reverses drug-induced mitochondrial and hepatocyte injury by promoting mitochondrial fusion and function

Kang, SWS; Haydar, Ghada; Taniane, Caitlin; Farrell, Geoffrey; Arias, IM; Lippincott-Schwartz, Jennifer; Fu, Dong

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Mitochondrial damage is the major factor underlying drug-induced liver disease but whether conditions that thwart mitochondrial injury can prevent or reverse drug-induced liver damage is unclear. A key molecule regulating mitochondria quality control is AMP activated kinase (AMPK). When activated, AMPK causes mitochondria to elongate/fuse and proliferate, with mitochondria now producing more ATP and less reactive oxygen species. Autophagy is also triggered, a process capable of removing...[Show more]

dc.contributor.authorKang, SWS
dc.contributor.authorHaydar, Ghada
dc.contributor.authorTaniane, Caitlin
dc.contributor.authorFarrell, Geoffrey
dc.contributor.authorArias, IM
dc.contributor.authorLippincott-Schwartz, Jennifer
dc.contributor.authorFu, Dong
dc.date.accessioned2018-11-29T22:56:14Z
dc.date.available2018-11-29T22:56:14Z
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/1885/153450
dc.description.abstractMitochondrial damage is the major factor underlying drug-induced liver disease but whether conditions that thwart mitochondrial injury can prevent or reverse drug-induced liver damage is unclear. A key molecule regulating mitochondria quality control is AMP activated kinase (AMPK). When activated, AMPK causes mitochondria to elongate/fuse and proliferate, with mitochondria now producing more ATP and less reactive oxygen species. Autophagy is also triggered, a process capable of removing damaged/defective mitochondria. To explore whether AMPK activation could potentially prevent or reverse the effects of drug-induced mitochondrial and hepatocellular damage, we added an AMPK activator to collagen sandwich cultures of rat and human hepatocytes exposed to the hepatotoxic drugs, acetaminophen or diclofenac. In the absence of AMPK activation, the drugs caused hepatocytes to lose polarized morphology and have significantly decreased ATP levels and viability. At the subcellular level, mitochondria underwent fragmentation and had decreased membrane potential due to decreased expression of the mitochondrial fusion proteins Mfn1, 2 and/or Opa1. Adding AICAR, a specific AMPK activator, at the time of drug exposure prevented and reversed these effects. The mitochondria became highly fused and ATP production increased, and hepatocytes maintained polarized morphology. In exploring the mechanism responsible for this preventive and reversal effect, we found that AMPK activation prevented drug-mediated decreases in Mfn1, 2 and Opa1. AMPK activation also stimulated autophagy/mitophagy, most significantly in acetaminophen-treated cells. These results suggest that activation of AMPK prevents/reverses drug-induced mitochondrial and hepatocellular damage through regulation of mitochondrial fusion and autophagy, making it a potentially valuable approach for treatment of drug-induced liver injury.
dc.format.mimetypeapplication/pdf
dc.publisherPublic Library of Science
dc.sourcePLOS ONE (Public Library of Science)
dc.titleAMPK Activation prevents and reverses drug-induced mitochondrial and hepatocyte injury by promoting mitochondrial fusion and function
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume11
dc.date.issued2016
local.identifier.absfor111506 - Toxicology (incl. Clinical Toxicology)
local.identifier.ariespublicationU3488905xPUB25006
local.type.statusPublished Version
local.contributor.affiliationKang, SWS, The University of Sydney
local.contributor.affiliationHaydar, Ghada, The University of Sydney
local.contributor.affiliationTaniane, Caitlin, The University of Sydney
local.contributor.affiliationFarrell, Geoffrey, College of Health and Medicine, ANU
local.contributor.affiliationArias, IM, National Institutes of Health
local.contributor.affiliationLippincott-Schwartz, Jennifer, Howard Hughes Medical Institute
local.contributor.affiliationFu, Dong, The University of Sydney
local.bibliographicCitation.issue10
local.identifier.doi10.1371/journal.pone.0165638
dc.date.updated2018-11-29T08:10:52Z
local.identifier.scopusID2-s2.0-84993928897
local.identifier.thomsonID000389537000039
dcterms.accessRightsOpen Access
CollectionsANU Research Publications

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