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Metformin Restores Parkin-Mediated Mitophagy, Suppressed by Cytosolic p53

DC FieldValueLanguage
dc.contributor.author강은석-
dc.contributor.author이병완-
dc.contributor.author이용호-
dc.contributor.author차봉수-
dc.contributor.author이우경-
dc.date.accessioned2017-02-24T08:10:20Z-
dc.date.available2017-02-24T08:10:20Z-
dc.date.issued2016-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/146572-
dc.description.abstractMetformin is known to alleviate hepatosteatosis by inducing 5' adenosine monophosphate (AMP)-kinase-independent, sirtuin 1 (SIRT1)-mediated autophagy. Dysfunctional mitophagy in response to glucolipotoxicities might play an important role in hepatosteatosis. Here, we investigated the mechanism by which metformin induces mitophagy through restoration of the suppressed Parkin-mediated mitophagy. To this end, our ob/ob mice were divided into three groups: (1) ad libitum feeding of a standard chow diet; (2) intraperitoneal injections of metformin 300 mg/kg; and (3) 3 g/day caloric restriction (CR). HepG2 cells were treated with palmitate (PA) plus high glucose in the absence or presence of metformin. We detected enhanced mitophagy in ob/ob mice treated with metformin or CR, whereas mitochondrial spheroids were observed in mice fed ad libitum. Metabolically stressed ob/ob mice and PA-treated HepG2 cells showed an increase in expression of endoplasmic reticulum (ER) stress markers and cytosolic p53. Cytosolic p53 inhibited mitophagy by disturbing the mitochondrial translocation of Parkin, as demonstrated by immunoprecipitation. However, metformin decreased ER stress and p53 expression, resulting in induction of Parkin-mediated mitophagy. Furthermore, pifithrin-α, a specific inhibitor of p53, increased mitochondrial incorporation into autophagosomes. Taken together, these results indicate that metformin treatment facilitates Parkin-mediated mitophagy rather than mitochondrial spheroid formation by decreasing the inhibitory interaction with cytosolic p53 and increasing degradation of mitofusins.-
dc.description.statementOfResponsibilityopen-
dc.format.extentE122-
dc.languageEnglish-
dc.publisherMDPI-
dc.relation.isPartOfInternational Journal of Molecular Sciences-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/2.0/kr/-
dc.subject.MESHAnimals-
dc.subject.MESHBenzothiazoles/pharmacology-
dc.subject.MESHCaloric Restriction-
dc.subject.MESHCell Survival/drug effects-
dc.subject.MESHDiet-
dc.subject.MESHEndoplasmic Reticulum Stress/drug effects-
dc.subject.MESHEndoplasmic Reticulum Stress/genetics-
dc.subject.MESHFatty Liver/drug therapy*-
dc.subject.MESHFatty Liver/genetics-
dc.subject.MESHFatty Liver/metabolism-
dc.subject.MESHFatty Liver/pathology-
dc.subject.MESHGene Expression Regulation-
dc.subject.MESHGlucose/pharmacology-
dc.subject.MESHHep G2 Cells-
dc.subject.MESHHumans-
dc.subject.MESHHypoglycemic Agents/pharmacology*-
dc.subject.MESHMetformin/pharmacology*-
dc.subject.MESHMice-
dc.subject.MESHMice, Obese-
dc.subject.MESHMitochondria/drug effects-
dc.subject.MESHMitochondria/metabolism-
dc.subject.MESHMitochondria/ultrastructure-
dc.subject.MESHMitochondrial Degradation/drug effects-
dc.subject.MESHPalmitic Acid/pharmacology-
dc.subject.MESHSignal Transduction-
dc.subject.MESHSirtuin 1/genetics-
dc.subject.MESHSirtuin 1/metabolism-
dc.subject.MESHToluene/analogs & derivatives-
dc.subject.MESHToluene/pharmacology-
dc.subject.MESHTumor Suppressor Protein p53/genetics*-
dc.subject.MESHTumor Suppressor Protein p53/metabolism-
dc.subject.MESHUbiquitin-Protein Ligases/genetics*-
dc.subject.MESHUbiquitin-Protein Ligases/metabolism-
dc.titleMetformin Restores Parkin-Mediated Mitophagy, Suppressed by Cytosolic p53-
dc.typeArticle-
dc.publisher.locationSwitzerland-
dc.contributor.collegeCollege of Medicine-
dc.contributor.departmentDept. of Internal Medicine-
dc.contributor.googleauthorYoung Mi Song-
dc.contributor.googleauthorWoo Kyung Lee-
dc.contributor.googleauthorYong-ho Lee-
dc.contributor.googleauthorEun Seok Kang-
dc.contributor.googleauthorBong-Soo Cha-
dc.contributor.googleauthorByung-Wan Lee-
dc.identifier.doi10.3390/ijms17010122-
dc.contributor.localIdA00068-
dc.contributor.localIdA02796-
dc.contributor.localIdA02989-
dc.contributor.localIdA03996-
dc.contributor.localIdA02991-
dc.relation.journalcodeJ01133-
dc.identifier.eissn1422-0067-
dc.identifier.pmid26784190-
dc.subject.keywordParkin-
dc.subject.keywordmetformin-
dc.subject.keywordmitochondrial spheroid-
dc.subject.keywordmitophagy-
dc.subject.keywordp53-
dc.contributor.alternativeNameKang, Eun Seok-
dc.contributor.alternativeNameLee, Byung Wan-
dc.contributor.alternativeNameLee, Yong Ho-
dc.contributor.alternativeNameCha, Bong Soo-
dc.contributor.affiliatedAuthorKang, Eun Seok-
dc.contributor.affiliatedAuthorLee, Byung Wan-
dc.contributor.affiliatedAuthorLee, Yong Ho-
dc.contributor.affiliatedAuthorCha, Bong Soo-
dc.citation.volume17-
dc.citation.number1-
dc.citation.startPage122-
dc.identifier.bibliographicCitationInternational Journal of Molecular Sciences, Vol.17(1) : 122, 2016-
dc.date.modified2017-02-24-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers

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