0 16

Cited 0 times in

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

Authors
 Eugen Widmeier  ;  Seyoung Yu  ;  Anish Nag  ;  Youn Wook Chung  ;  Makiko Nakayama  ;  Lucía Fernández-Del-Río  ;  Hannah Hugo  ;  David Schapiro  ;  Florian Buerger  ;  Won-Il Choi  ;  Martin Helmstädter  ;  Jae-Woo Kim  ;  Ji-Hwan Ryu  ;  Min Goo Lee  ;  Catherine F Clarke  ;  Friedhelm Hildebrandt  ;  Heon Yung Gee 
Citation
 JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol.31(6) : 1191-1211, 2020-06 
Journal Title
 JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 
ISSN
 1046-6673 
Issue Date
2020-06
Keywords
2,4-dihydroxybenzoic acid ; ADCK4 ; Q complex ; coenzyme Q10 ; steroid-resistant nephrotic syndrome
Abstract
Background: 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.
Full Text
https://jasn.asnjournals.org/content/31/6/1191.long
DOI
10.1681/ASN.2019070756
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
Yonsei Authors
Kim, Jae Woo(김재우) ORCID logo https://orcid.org/0000-0001-5456-9495
Ryu, Ji Hwan(유지환)
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
Chung, Youn Wook(정연욱) ORCID logo https://orcid.org/0000-0002-4382-1410
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/179461
사서에게 알리기
  feedback

qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse

Links