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

Abstract

<jats:title>Abstract</jats:title><jats:p><jats:italic>ADCK4</jats:italic> mutations usually manifest as steroid-resistant nephrotic syndrome, and cause coenzyme Q<jats:sub>10</jats:sub> (CoQ<jats:sub>10</jats:sub>) deficiency. However, the function of ADCK4 remains obscure. We investigated ADCK4 function using mouse and cell models. Podocyte-specific <jats:italic>Adck4</jats:italic> 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 CoQ<jats:sub>10</jats:sub> precursor molecule. ADCK4 knockout podocytes exhibited significantly decreased CoQ<jats:sub>10</jats:sub> 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 CoQ<jats:sub>10</jats:sub> 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 CoQ<jats:sub>10</jats:sub> biosynthesis and mitochondrial function in podocytes.</jats:p>

Mitochondrial Disease and the Kidney With a Special Focus on CoQ10 Deficiency

“…106 Moreover, COQ8B/ADCK4 is required for CoQ 10 biosynthesis and mitochondrial function in podocytes. 121 Compared to other CoQ 10 biosynthesis defects, mutations in COQ8B/ADCK4 seem to result in a less severe clinical entity, with a more prominent kidney phenotype, higher age at onset of SRNS, and good patient survival owing to the lack of extrarenal manifestations. The selective glomerular phenotype of patients with COQ8B/ADCK4 mutations may be the result of relative enrichment of COQ8B/ADCK4 and lacking expression of the related protein COQ8A/ADCK3 in podocytes, whereas COQ8A/ADCK3 expression exceeds that of COQ8B/ADCK4 in most other body tissues.…”

“…130 A potential role for 2,4diHB was suggested for the treatment of CoQ10 deficiency caused by COQ8B/ADCK4 mutations as well. 121 Moreover, Ozeir et al demonstrated that analogs of 4-HB can bypass a deficient CoQ biosynthetic enzyme. 103 Additionally, hydroxylated analogues of 4-HB, 3,4-dihydroxybenzoic acid and/or vanillic acid were marked as a potential therapeutic intervention for CoQ 10 deficiency due to a COQ6 mutation.…”

Mitochondria Matter: A Critical Role of ADCK4 in Stabilizing the CoQ Complex in Podocytes in Steroid-Resistant Nephrotic Syndrome

“…In this issue of JASN, a study by Widmeier et al 6 demonstrates that Adck4 function is required for podocyte maintenance and homeostasis in mice by stabilizing the CoQ complex ( Figure 1). Using whole-exome sequencing in patients with SRNS, this group was first to identify homozygous loss-of-function mutations in ADCK4 as disease causative.…”

“…Interestingly, a group of mutations in genes involved in coenzyme Q 10 (CoQ 10 ; ubiquinone) biosynthesis, such as COQ 6 ; COQ 2 ; prenyl diphosphate synthase, subunit 2 (PDSS2); and ADCK4 (COQ8B), have also been associated with childhood-onset FSGS and SRNS. CoQ 10 is a component of the mitochondrial inner membrane and plays important roles in supporting electron transport of oxidative phosphorylation (OXPHOS), protection from oxidative stress, and activation of mitochondrial enzymes required in metabolic pathways, including pyrimidine synthesis.…”

“…The work by Widmeier et al 6 emphasizes the effect of impaired electron transport in podocytes in the maintenance of the glomerular filtration barrier. These findings are in agreement with recent research demonstrating that the loss-offunction mutation of the complex IV assembly cofactor heme A:farnesyltransferase (COX10) in cells of the developing nephrons was sufficient to cause FSGS.…”