Probucol ameliorates renal and metabolic sequelae of primary CoQ deficiency in Pdss2 mutant mice

Abstract

Therapy of mitochondrial respiratory chain diseases is complicated by limited understanding of cellular mechanisms that cause the widely variable clinical findings. Here, we show that focal segmental glomerulopathy-like kidney disease in Pdss2 mutant animals with primary coenzyme Q (CoQ) deficiency is significantly ameliorated by oral treatment with probucol (1% w/w). Preventative effects in missense mutant mice are similar whether fed probucol from weaning or for 3 weeks prior to typical nephritis onset. Furthermore, treating symptomatic animals for 2 weeks with probucol significantly reduces albuminuria. Probucol has a more pronounced health benefit than high-dose CoQ10 supplementation and uniquely restores CoQ9 content in mutant kidney. Probucol substantially mitigates transcriptional alterations across many intermediary metabolic domains, including peroxisome proliferator-activated receptor (PPAR) pathway signaling. Probucol's beneficial effects on the renal and metabolic manifestations of Pdss2 disease occur despite modest induction of oxidant stress and appear independent of its hypolipidemic effects. Rather, decreased CoQ9 content and altered PPAR pathway signaling appear, respectively, to orchestrate the glomerular and global metabolic consequences of primary CoQ deficiency, which are both preventable and treatable with oral probucol therapy.

Mitochondrial function and lifespan of mice with controlled ubiquinone biosynthesis

“…In addition, secondary UQ deficiencies due to mutations in other genes including in mtDNA are frequently observed in patients with mitochondrial disease syndrome 57,58 . To date, the only available treatment for the disease is UQ supplementation, but its efficacy is variable and limited, presumably because of very poor uptake by most tissues except the liver [13][14][15]17,19,[59][60][61] .…”

Resveratrol and para-coumarate serve as ring precursors for coenzyme Q biosynthesis

“…The RP-HPLC-MS/MS analyses were performed as previously described for determination of Q 6 in yeast lipid extracts ( 11,18 ) and determination of Q 9 and Q 10 in mammalian lipid extracts ( 28,29 ). Briefl y, a 4000 QTRAP linear MS/MS spectrometer from Applied Biosystems (Foster City, CA) was used.…”

ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption

“…Lipid extracts were prepared by addition of 1.2 ml methanol, followed by 1.8 ml petroleum ether. Diethoxy-CoQ10 served as an internal standard (39). A typical standard curve contains 5 standards with 7.2 pmol, 20 pmol, 72 pmol, 140 pmol, and 400 pmol of CoQ10, respectively.…”