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ADCK4 Deficiency Destabilizes the Coenzyme Q Complex, Which Is Rescued by 2,4-Dihydroxybenzoic Acid Treatment

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dc.contributor.author유지환-
dc.contributor.author정연욱-
dc.contributor.author김재우-
dc.contributor.author이민구-
dc.contributor.author지헌영-
dc.date.accessioned2020-09-29T01:16:38Z-
dc.date.available2020-09-29T01:16:38Z-
dc.date.issued2020-06-
dc.identifier.issn1046-6673-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/179461-
dc.description.abstractBackground: Mutations in ADCK4 (aarF domain containing kinase 4) generally manifest as steroid-resistant nephrotic syndrome and induce coenzyme Q10 (CoQ10) deficiency. However, the molecular mechanisms underlying steroid-resistant nephrotic syndrome resulting from ADCK4 mutations are not well understood, largely because the function of ADCK4 remains unknown. Methods: To elucidate the ADCK4's function in podocytes, we generated a podocyte-specific, Adck4-knockout mouse model and a human podocyte cell line featuring knockout of ADCK4. These knockout mice and podocytes were then treated with 2,4-dihydroxybenzoic acid (2,4-diHB), a CoQ10 precursor analogue, or with a vehicle only. We also performed proteomic mass spectrometry analysis to further elucidate ADCK4's function. Results: Absence of Adck4 in mouse podocytes caused FSGS and albuminuria, recapitulating features of nephrotic syndrome caused by ADCK4 mutations. In vitro studies revealed that ADCK4-knockout podocytes had significantly reduced CoQ10 concentration, respiratory chain activity, and mitochondrial potential, and subsequently displayed an increase in the number of dysmorphic mitochondria. However, treatment of 3-month-old knockout mice or ADCK4-knockout cells with 2,4-diHB prevented the development of renal dysfunction and reversed mitochondrial dysfunction in podocytes. Moreover, ADCK4 interacted with mitochondrial proteins such as COQ5, as well as cytoplasmic proteins such as myosin and heat shock proteins. Thus, ADCK4 knockout decreased the COQ complex level, but overexpression of ADCK4 in ADCK4-knockout podocytes transfected with wild-type ADCK4 rescued the COQ5 level. Conclusions: Our study shows that ADCK4 is required for CoQ10 biosynthesis and mitochondrial function in podocytes, and suggests that ADCK4 in podocytes stabilizes proteins in complex Q in podocytes. Our study also suggests a potential treatment strategy for nephrotic syndrome resulting from ADCK4 mutations.-
dc.description.statementOfResponsibilityrestriction-
dc.languageEnglish-
dc.publisherAmerican Society of Nephrology-
dc.relation.isPartOfJOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.titleADCK4 Deficiency Destabilizes the Coenzyme Q Complex, Which Is Rescued by 2,4-Dihydroxybenzoic Acid Treatment-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentBioMedical Science Institute (의생명과학부)-
dc.contributor.googleauthorEugen Widmeier-
dc.contributor.googleauthorSeyoung Yu-
dc.contributor.googleauthorAnish Nag-
dc.contributor.googleauthorYoun Wook Chung-
dc.contributor.googleauthorMakiko Nakayama-
dc.contributor.googleauthorLucía Fernández-Del-Río-
dc.contributor.googleauthorHannah Hugo-
dc.contributor.googleauthorDavid Schapiro-
dc.contributor.googleauthorFlorian Buerger-
dc.contributor.googleauthorWon-Il Choi-
dc.contributor.googleauthorMartin Helmstädter-
dc.contributor.googleauthorJae-Woo Kim-
dc.contributor.googleauthorJi-Hwan Ryu-
dc.contributor.googleauthorMin Goo Lee-
dc.contributor.googleauthorCatherine F Clarke-
dc.contributor.googleauthorFriedhelm Hildebrandt-
dc.contributor.googleauthorHeon Yung Gee-
dc.identifier.doi10.1681/ASN.2019070756-
dc.contributor.localIdA04611-
dc.contributor.localIdA03654-
dc.contributor.localIdA00865-
dc.contributor.localIdA02781-
dc.contributor.localIdA03971-
dc.relation.journalcodeJ01779-
dc.identifier.eissn1533-3450-
dc.identifier.pmid32381600-
dc.identifier.urlhttps://jasn.asnjournals.org/content/31/6/1191.long-
dc.subject.keyword2,4-dihydroxybenzoic acid-
dc.subject.keywordADCK4-
dc.subject.keywordQ complex-
dc.subject.keywordcoenzyme Q10-
dc.subject.keywordsteroid-resistant nephrotic syndrome-
dc.contributor.alternativeNameRyu, Ji Hwan-
dc.contributor.affiliatedAuthor유지환-
dc.contributor.affiliatedAuthor정연욱-
dc.contributor.affiliatedAuthor김재우-
dc.contributor.affiliatedAuthor이민구-
dc.contributor.affiliatedAuthor지헌영-
dc.citation.volume31-
dc.citation.number6-
dc.citation.startPage1191-
dc.citation.endPage1211-
dc.identifier.bibliographicCitationJOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol.31(6) : 1191-1211, 2020-06-
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers

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