title: Disruption of renal tubular mitochondrial quality control by Myo-inositol oxygenase in diabetic kidney disease.
abstract: Diabetic kidney disease (DKD) is associated with oxidative stress and mitochondrial injury. Myo-inositol oxygenase (MIOX), a tubular-specific enzyme, modulates redox imbalance and apoptosis in tubular cells in diabetes, but these mechanisms remain unclear. We investigated the role of MIOX in perturbation of mitochondrial quality control, including mitochondrial dynamics and autophagy/mitophagy, under high-glucose (HG) ambience or a diabetic state. HK-2 or LLC-PK1 cells subjected to HG exhibited an upregulation of MIOX accompanied by mitochondrial fragmentation and depolarization, inhibition of autophagy/mitophagy, and altered expression of mitochondrial dynamic and mitophagic proteins. Furthermore, dysfunctional mitochondria accumulated in the cytoplasm, which coincided with increased reactive oxygen species generation, Bax activation, cytochrome C release, and apoptosis. Overexpression of MIOX in LLC-PK1 cells enhanced the effects of HG, whereas MIOX siRNA or d-glucarate, an inhibitor of MIOX, partially reversed these perturbations. Moreover, decreasing the expression of MIOX under HG ambience increased PTEN-induced putative kinase 1 expression and the dependent mitofusin-2-Parkin interaction. In tubules of diabetic mice, increased MIOX expression and mitochondrial fragmentation and defective autophagy were observed. Dietary supplementation of d-glucarate in diabetic mice decreased MIOX expression, attenuated tubular damage, and improved renal functions. Notably, d-glucarate administration also partially attenuated mitochondrial fragmentation, oxidative stress, and apoptosis and restored autophagy/mitophagy in the tubular cells of these mice. These results suggest a novel mechanism linking MIOX to impaired mitochondrial quality control during tubular injury in the pathogenesis of DKD and suggest d-glucarate as a potential therapeutic agent for the amelioration of DKD.
authors.affiliation: Departments of Pathology and Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhan
authors.affiliation: Departments of Pathology and Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Irtaza M
authors.initials: IM
authors.lastname: Usman
authors.affiliation: Departments of Pathology and Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Lin
authors.initials: L
authors.lastname: Sun
authors.affiliation: Departments of Pathology and Medicine, Northwestern University, Chicago, Illinois y-kanwar@northwestern.edu.
authors.forename: Yashpal S
authors.initials: YS
authors.lastname: Kanwar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005965:Glucuronates / Q000494:pharmacology*; D007150:Immunohistochemistry; D050562:Inositol Oxygenase / Q000235:genetics* / Q000378:metabolism; D007677:Kidney Function Tests; D007684:Kidney Tubules / Q000201:enzymology / Q000378:metabolism*; D018374:LLC-PK1 Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism; D012680:Sensitivity and Specificity; D013311:Streptozocin / Q000494:pharmacology; D013552:Swine; D015854:Up-Regulation
chemical_list: D005965:Glucuronates; D017382:Reactive Oxygen Species; D013311:Streptozocin; D050562:Inositol Oxygenase
keywords: apoptosis; diabetic nephropathy; mitochondria; oxidative stress; tubule cells