ADCK4 deficiency destabilizes the coenzyme Q complex, which is rescued by 2,4-dihydroxybenzoic acid treatment

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

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)


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 podocyteswere then treated with 2,4-dihydroxybenzoic acid (2,4-diHB), aCoQ10 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.

Original languageEnglish
Pages (from-to)1191-1211
Number of pages21
JournalJournal of the American Society of Nephrology
Issue number6
Publication statusPublished - 2020 Jun

Bibliographical note

Publisher Copyright:
Copyright © 2020 by the American Society of Nephrology.

All Science Journal Classification (ASJC) codes

  • General Medicine


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