Proteomic Approaches to Identify and Characterize Alterations to the Mitochondrial Proteome in Alcoholic Liver Disease

Bailey, Shannon M.; Andringa, Kelly K.; Landar, Aimee; Darley‐Usmar, Victor

doi:10.1007/978-1-59745-242-7_24

Cited by 14 publications

(9 citation statements)

References 19 publications

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“…Mitochondria were isolated from the kidney with homogenization followed by multiple centrifugations at 700 g , 7800 g and 10000 g in ice-cold isolation buffer containing 50 mM Tris/HCl, pH 7.4, 250 mM sucrose, 5 mM EDTA and protease inhibitors as described previously [28]. Respiratory capacity of isolated mitochondria was assessed in a Hansatech Oxygraph in mitochondrial respiration medium (2.5 mM Hepes, pH 7.4, 120 mM KCl, 5 mM KH 2 PO 4 , 1 mM EGTA, 10.7 mM MgCl 2 and 2.5 mM sucrose) and 5 mM succinate/0.5 mM ADP at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

Prevention of diabetic nephropathy in Ins2+/−AkitaJ mice by the mitochondria-targeted therapy MitoQ

Chacko

Reily

Srivastava

et al. 2010

Biochemical Journal

190

122

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Mitochondrial production of ROS (reactive oxygen species) is thought to be associated with the cellular damage resulting from chronic exposure to high glucose in long-term diabetic patients. We hypothesized that a mitochondria-targeted antioxidant would prevent kidney damage in the Ins2+/−AkitaJ mouse model (Akita mice) of Type 1 diabetes. To test this we orally administered a mitochondria-targeted ubiquinone (MitoQ) over a 12-week period and assessed tubular and glomerular function. Fibrosis and pro-fibrotic signalling pathways were determined by immunohistochemical analysis, and mitochondria were isolated from the kidney for functional assessment. MitoQ treatment improved tubular and glomerular function in the Ins2+/−AkitaJ mice. MitoQ did not have a significant effect on plasma creatinine levels, but decreased urinary albumin levels to the same level as non-diabetic controls. Consistent with previous studies, renal mitochondrial function showed no significant change between any of the diabetic or wild-type groups. Importantly, interstitial fibrosis and glomerular damage were significantly reduced in the treated animals. The pro-fibrotic transcription factors phospho-Smad2/3 and β-catenin showed a nuclear accumulation in the Ins2+/−AkitaJ mice, which was prevented by MitoQ treatment. These results support the hypothesis that mitochondrially targeted therapies may be beneficial in the treatment of diabetic nephropathy. They also highlight a relatively unexplored aspect of mitochondrial ROS signalling in the control of fibrosis.

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Section: Methodsmentioning

confidence: 99%

Prevention of diabetic nephropathy in Ins2+/−AkitaJ mice by the mitochondria-targeted therapy MitoQ

Chacko

Reily

Srivastava

et al. 2010

Biochemical Journal

190

122

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“…44 The mitochondrial protein concentration was determined by Bradford protein assay. 45 It is imperative that mitochondria used for proteomics studies are isolated by methodologies that result in functional and pure mitochondrial preparations.…”

Section: Mitochondria Isolationmentioning

confidence: 99%

Inhibition to DRP1 translocation can mitigate p38 MAPK-signaling pathway activation in GMC induced by hyperglycemia

Zhang

Tang

et al. 2015

Renal Failure

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Diabetic nephropathy (DN) is a serious complication of diabetes with a poorly defined etiology and limited treatment options. Early intervention is a key to preventing the progression of DN. Dynamin-related protein 1 (DRP1) regulates mitochondrial morphology by promoting its fission and is involved in the pathogenesis of numerous diseases. Furthermore, DRP1 is also closely associated with the development of diabetes, but its functional role in DN remains unknown. This study investigated the effect of DRP1 on early stage of DN. DRP1 expression has increased significantly in glomerular mesangial cell (GMC), which is cultivated in high glucose (HG). Ultramicrostructural changes of nephrons, expression of collagen IV and phosph-p38, ROS production, and mitochondrial function were evaluated and, at the same time, were compared with glomerular mesangial cell (GMC) cultured in normal-glucose (NG), mannitol, and a medium with mitochondrial division inhibitor 1 (Midivi-1). Endogenous DRP1 expression increased in DN. Compared to the control groups ofNG and mannitol, overexpression of DRP1 destroyed pathological changes typical of the GMC, like accumulation of extracellular matrix, and an increase in mitochondria division. In addition, Overexpression of DRP1 promoted the activation of p38, the accumulation of ROS, mitochondrial dysfunction, and the synthesis of collagen IV, and all these changes are suppressed by Midivi-1. This study demonstrates that DRP1 overexpression can accelerate pathological changes in the GMC cultured in HG. Further studies are needed to clarify the underlying mechanism of this destructive function.

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“…As shown in several mitochondrial proteome works [6,7], a lot of mitochondrial proteins including oxoglutarate dehydrogenase (lipoamide), ketoacyl-CoA thiolase, etc. were regulated due to ethanol-dependent hepatotoxicity [6].…”

Section: Introductionmentioning

confidence: 99%

A dynamic plasma membrane proteome analysis of alcohol-induced liver cirrhosis

Jia

Feng

et al. 2012

Proteome Sci

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Alcohol-induced injury has become one of the major causes for liver cirrhosis. However, the molecular mechanisms of ethanol-induced injury are not fully understood. To this end, we performed a dynamic plasma membrane proteomic research on rat model. A rat model from hepatitis to liver cirrhosis was developed. Plasma membrane from liver tissue with liver fibrosis stage of 2 and 4 (S2 and S4) was purified by sucrose density gradient centrifugation. Its purification was verified by western blotting. Proteins from plasma membrane were separated by two-dimensional electrophoresis (2DE) and differentially expressed proteins were identified by tandem mass spectrometry. 16 consistent differentially expressed proteins from S2 to S4 were identified by mass spectrometry. The expression of differentially expressed proteins annexin A6 and annexin A3 were verified by western blotting, and annexin A3 was futher verified by immunohistochemistry. Our research suggests a possible mechanism by which ethanol alters protein expression to enhance the liver fibrosis progression. These differentially expressed proteins might be new drug targets for treating alcoholic liver cirrhosis.

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Proteomic Approaches to Identify and Characterize Alterations to the Mitochondrial Proteome in Alcoholic Liver Disease

Cited by 14 publications

References 19 publications

Prevention of diabetic nephropathy in Ins2+/−AkitaJ mice by the mitochondria-targeted therapy MitoQ

Prevention of diabetic nephropathy in Ins2+/−AkitaJ mice by the mitochondria-targeted therapy MitoQ

Inhibition to DRP1 translocation can mitigate p38 MAPK-signaling pathway activation in GMC induced by hyperglycemia

A dynamic plasma membrane proteome analysis of alcohol-induced liver cirrhosis

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