RT Journal Article
SR Electronic
T1 ADCK4 deficiency destabilizes the coenzyme Q complex, which is rescued by 2,4-dihydroxybenzoic acid treatment
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 712323
DO 10.1101/712323
A1 Eugen Widmeier
A1 Seyoung Yu
A1 Anish Nag
A1 Youn Wook Chung
A1 Makiko Nakayama
A1 Hannah Hugo
A1 Florian Buerger
A1 David Schapiro
A1 Won-Il Choi
A1 Jae-woo Kim
A1 Ji-Hwan Ryu
A1 Min Goo Lee
A1 Catherine F. Clarke
A1 Friedhelm Hildebrandt
A1 Heon Yung Gee
YR 2019
UL http://biorxiv.org/content/early/2019/07/23/712323.abstract
AB ADCK4 mutations usually manifest as steroid-resistant nephrotic syndrome, and cause coenzyme Q10 (CoQ10) deficiency. However, the function of ADCK4 remains obscure. We investigated ADCK4 function using mouse and cell models. Podocyte-specific Adck4 deletion in mice significantly reduced survival and caused severe focal segmental glomerular sclerosis with extensive interstitial fibrosis and tubular atrophy, which were prevented by treatment with 2,4-dihydroxybenzoic acid (2,4-diHB), an analog of CoQ10 precursor molecule. ADCK4 knockout podocytes exhibited significantly decreased CoQ10 level, respiratory chain activity, mitochondrial potential, and dysmorphic mitochondria with loss of cristae formation, which were rescued by 2,4-diHB treatment, thus attributing these phenotypes to decreased CoQ10 levels. ADCK4 interacted with mitochondrial proteins including COQ5, and also cytoplasmic proteins including myosin and heat shock proteins. ADCK4 knockout decreased COQ complex levels, and the COQ5 level was rescued by ADCK4 overexpression in ADCK4 knockout podocytes. Overall, ADCK4 is required for CoQ10 biosynthesis and mitochondrial function in podocytes.