Falk 2012 EMBO Mol Med
| Falk MJ, Polyak E, Zhang Z, Peng M, King R, Maltzman JS, Okwuego E, Horyn O, Nakamaru-Ogiso E, Ostrovsky J, Xie LX, Chen JY, Marbois B, Nissim I, Clarke CF, Gasser DL (2012) Probucol ameliorates renal and metabolic sequelae of primary CoQ deficiency in Pdss2 mutant mice. EMBO Mol Med 3: 410-427. |
Falk MJ, Polyak E, Zhang Z, Peng M, King R, Maltzman JS, Okwuego E, Horyn O, Nakamaru-Ogiso E, Ostrovsky J, Xie LX, Chen JY, Marbois B, Nissim I, Clarke CF, Gasser DL (2012) EMBO Mol Med
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 CoQ(10) supplementation and uniquely restores CoQ(9) 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 CoQ(9) 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. • Keywords: Pdss2 mutant, coenzyme Q (CoQ) deficiency, probucol, peroxisome proliferator-activated receptor (PPAR)
• O2k-Network Lab: US PA Philadelphia Falk MJ
Labels:
Stress:Mitochondrial Disease; Degenerative Disease and Defect"Mitochondrial Disease; Degenerative Disease and Defect" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property., Genetic Defect; Knockdown; Overexpression"Genetic Defect; Knockdown; Overexpression" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property. Organism: Mouse Tissue;cell: Skeletal muscle Preparation: Permeabilized tissue
Coupling state: OXPHOS
HRR: Oxygraph-2k
