scholarly journals Proteomic alterations of distinct mitochondrial subpopulations in the type 1 diabetic heart: contribution of protein import dysfunction

2011 ◽  
Vol 300 (2) ◽  
pp. R186-R200 ◽  
Author(s):  
Walter A. Baseler ◽  
Erinne R. Dabkowski ◽  
Courtney L. Williamson ◽  
Tara L. Croston ◽  
Dharendra Thapa ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Protein Import ◽  
Adenine Nucleotide ◽  
Mitochondrial Protein ◽  
Diabetic Heart ◽  
Acid Oxidation ◽  
Diabetic Patients ◽  
Mitochondrial Protein Import ◽  
Increased Risk

Diabetic cardiomyopathy is associated with increased risk of heart failure in type 1 diabetic patients. Mitochondrial dysfunction is suggested as an underlying contributor to diabetic cardiomyopathy. Cardiac mitochondria are characterized by subcellular spatial locale, including mitochondria located beneath the sarcolemma, subsarcolemmal mitochondria (SSM), and mitochondria situated between the myofibrils, interfibrillar mitochondria (IFM). The goal of this study was to determine whether type 1 diabetic insult in the heart influences proteomic make-up of spatially distinct mitochondrial subpopulations and to evaluate the role of nuclear encoded mitochondrial protein import. Utilizing multiple proteomic approaches (iTRAQ and two-dimensional-differential in-gel electrophoresis), IFM proteomic make-up was impacted by type 1 diabetes mellitus to a greater extent than SSM, as evidenced by decreased abundance of fatty acid oxidation and electron transport chain proteins. Mitochondrial phosphate carrier and adenine nucleotide translocator, as well as inner membrane translocases, were decreased in the diabetic IFM ( P < 0.05 for both). Mitofilin, a protein involved in cristae morphology, was diminished in the diabetic IFM ( P < 0.05). Posttranslational modifications, including oxidations and deamidations, were most prevalent in the diabetic IFM. Mitochondrial heat shock protein 70 (mtHsp70) was significantly decreased in diabetic IFM ( P < 0.05). Mitochondrial protein import was decreased in the diabetic IFM with no change in the diabetic SSM ( P < 0.05). Taken together, these results indicate that mitochondrial proteomic alterations in the type 1 diabetic heart are more pronounced in the IFM. Further, proteomic alterations are associated with nuclear encoded mitochondrial protein import dysfunction and loss of an essential mitochondrial protein import constituent, mtHsp70, implicating this process in the pathogenesis of the diabetic heart.

scholarly journals Reversal of mitochondrial proteomic loss in Type 1 diabetic heart with overexpression of phospholipid hydroperoxide glutathione peroxidase

2013 ◽  
Vol 304 (7) ◽  
pp. R553-R565 ◽  
Author(s):  
Walter A. Baseler ◽  
Erinne R. Dabkowski ◽  
Rajaganapathi Jagannathan ◽  
Dharendra Thapa ◽  
Cody E. Nichols ◽  
...  
Keyword(s):  
Glutathione Peroxidase ◽  
Mitochondrial Dysfunction ◽  
Protein Import ◽  
Contractile Function ◽  
Tricarboxylic Acid Cycle ◽  
Mitochondrial Protein ◽  
Diabetic Heart ◽  
Phospholipid Hydroperoxide Glutathione Peroxidase ◽  
Mitochondrial Protein Import ◽  
Phospholipid Hydroperoxide

Mitochondrial dysfunction is a contributor to diabetic cardiomyopathy. Previously, we observed proteomic decrements within the inner mitochondrial membrane (IMM) and matrix of diabetic cardiac interfibrillar mitochondria (IFM) correlating with dysfunctional mitochondrial protein import. The goal of this study was to determine whether overexpression of mitochondria phospholipid hydroperoxide glutathione peroxidase 4 (mPHGPx), an antioxidant enzyme capable of scavenging membrane-associated lipid peroxides in the IMM, could reverse proteomic alterations, dysfunctional protein import, and ultimately, mitochondrial dysfunction associated with the diabetic heart. MPHGPx transgenic mice and controls were made diabetic by multiple low-dose streptozotocin injections and examined after 5 wk of hyperglycemia. Five weeks after hyperglycemia onset, in vivo analysis of cardiac contractile function revealed decreased ejection fraction and fractional shortening in diabetic hearts that was reversed with mPHGPx overexpression. MPHGPx overexpression increased electron transport chain function while attenuating hydrogen peroxide production and lipid peroxidation in diabetic mPHGPx IFM. MPHGPx overexpression lessened proteomic loss observed in diabetic IFM. Posttranslational modifications, including oxidations and deamidations, were attenuated in diabetic IFM with mPHGPx overexpression. Mitochondrial protein import dysfunction in diabetic IFM was reversed with mPHGPx overexpression correlating with protein import constituent preservation. Ingenuity Pathway Analyses indicated that oxidative phosphorylation, tricarboxylic acid cycle, and fatty acid oxidation processes most influenced in diabetic IFM were preserved by mPHGPx overexpression. Specific mitochondrial networks preserved included complex I and II, mitochondrial ultrastructure, and mitochondrial protein import. These results indicate that mPHGPx overexpression can preserve the mitochondrial proteome and provide cardioprotective benefits to the diabetic heart.

Abstract 362: Dysregulation of CPT2 Splicing in Diabetic Heart Disease

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Elizabeth Jaworski ◽  
Curtis Nutter ◽  
Sunil Verma ◽  
Vaibhav Deshmukh ◽  
Muge Kuyumucu-Martinez
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Diabetic Cardiomyopathy ◽  
Energy Production ◽  
Diabetic Heart ◽  
Acid Oxidation ◽  
Sequencing Analysis ◽  
Increased Risk ◽  
Exon 4

Diabetes mellitus is a group of metabolic diseases that are caused by elevated blood glucose levels. Individuals with diabetes have an increased risk of cardiovascular complications that include diabetic cardiomyopathy, hypertension, and coronary artery disease. Research has shown that hyperglycemia causes metabolic abnormalities in the heart such that cardiomyocytes are unable to utilize glucose for energy production due to reduced glucose intake, instead they solely depend on fatty acid oxidation for energy. Eventually, fatty acids accumulate and cause cardiac lipotoxicity, a presumed factor in the development of diabetic cardiomyopathy. Carnitine Pamitoyl Transferease 2 (CPT2) is one of the enzymes responsible for the transport of long-chain fatty acids into the mitochondria for fatty acid oxidation and energy production. CPT2 activity is elevated in diabetic hearts by mechanisms that are unclear. CPT2 is composed of 5 exons; the largest, exon 4 contains the transferase domain and is alternatively spliced in diabetes. In normal hearts, half of the CPT2 transcripts include exon 4 representing the active form of the enzyme. Through RNA sequencing analysis assay, we discovered that CPT2 is mis-spliced in diabetic hearts in a way that 70% of total CPT2 transcripts include the functional domain exon 4. The splicing change in CPT2 results in increased expression of the active CPT2 isoform in diabetic hearts. In summary, we identified a functionally important alternative splicing event in the CPT2 gene that may contribute to increased fatty acid oxidation and lipotoxicity in the diabetic heart.

scholarly journals Correction of an enzyme trafficking defect in hereditary kidney stone disease in vitro

2003 ◽  
Vol 374 (1) ◽  
pp. 79-87 ◽  
Author(s):  
Michael J. LUMB ◽  
Graeme M. BIRDSEY ◽  
Christopher J. DANPURE
Keyword(s):  
Kidney Stone ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Primary Hyperoxaluria ◽  
Stone Disease ◽  
Mitochondrial Protein Import ◽  
Primary Hyperoxaluria Type 1 ◽  
Kidney Stone Disease ◽  
Hyperoxaluria Type

In normal human hepatocytes, the intermediary-metabolic enzyme alanine:glyoxylate aminotransferase (AGT) is located within the peroxisomes. However, in approx. one-third of patients suffering from the hereditary kidney stone disease primary hyperoxaluria type 1, AGT is mistargeted to the mitochondria. AGT mistargeting results from the synergistic interaction between a common P11L (Pro11→Leu) polymorphism and a disease-specific G170R mutation. The polymorphism generates a functionally weak mitochondrial targeting sequence, the efficiency of which is increased by the mutation. The two substitutions together, but not in isolation, inhibit AGT dimerization, highlighting the different structural requirements of the peroxisomal and mitochondrial protein-import machineries. In the present study, we show that treatments known to increase the stability of proteins non-specifically (i.e. lowering the temperature from 37 to 30 °C or by the addition of glycerol) completely normalize the intracellular targeting of mutant AGT expressed in transfected COS cells. On the other hand, treatments known to decrease protein stability (e.g. increasing the temperature from 37 to 42 °C) exacerbate the targeting defect. Neither of the treatments affects the relative efficiencies of the peroxisomal and mitochondrial protein-import pathways intrinsically. Results are discussed in the light of the known structural requirements of the two protein trafficking pathways and the formulation of possible treatment strategies for primary hyperoxaluria type 1.

The effect of insulin pump therapy in retinal vasculature in type 1 diabetic patients

2021 ◽  
pp. 112067212199057
Author(s):  
Tomás de Oliveira Loureiro ◽  
João Nobre Cardoso ◽  
Carlos Diogo Pinheiro Lima Lopes ◽  
Ana Rita Carreira ◽  
Sandra Rodrigues-Barros ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Metabolic Control ◽  
Insulin Pump Therapy ◽  
Vascular Density ◽  
Diabetic Patients ◽  
Retinal Vasculature ◽  
Increased Risk ◽  
The Mean ◽  
Type 1 Diabetic Patients

Background/objectives: Continuous subcutaneous insulin infusion (CSII) is a treatment for type 1 diabetes that improves metabolic control and reduces micro and macrovascular complications. The aim of this study was to compare the effect of CSII versus traditional multiple daily injections (MDI) therapy on retinal vasculature. Methods: We performed a prospective study with type 1 diabetic patients with no prior history of ocular pathology other than mild diabetic retinopathy. The patients were divided into two groups according to their therapeutic modality (CSII vs MDI). The retinal nerve fiber layers thickness and vascular densities were compared between groups in both macula and optic disc. The correlations between vascular density and clinical features were also determined. Statistical significance was defined as p < 0.05. Results: The study included 52 eyes, 28 in the insulin CSII group. The mean age was 36.66 ± 12.97 years, with no difference between groups ( p = 0.49). The mean glycated hemoglobin (HbA1c) was found to be lower in the CSII group (7.1% ± 0.7 vs 7.5% ± 0.7 p < 0.01). The parafoveal vascular density was found to be higher in the CSII group (42.5% ± 0.4 vs 37.7% ± 0.6, p < 0.01). We found an inverse correlation between HbA1c value and parafoveal vascular densities ( p < 0.01, r = −0.50). Conclusion: We found that CSII provided better metabolic control than MDI and this seemed to result in higher parafoveal vascular density. As lower vascular density is associated with an increased risk of diabetic retinopathy, these results suggest that CSII could be the safest therapeutic option to prevent retinopathy.

scholarly journals Structural Basis of Presequence Recognition by the Mitochondrial Protein Import Receptor Tom20

Cell ◽  
2000 ◽  
Vol 100 (5) ◽  
pp. 551-560 ◽  
Author(s):  
Yoshito Abe ◽  
Toshihiro Shodai ◽  
Takanori Muto ◽  
Katsuyoshi Mihara ◽  
Hisayoshi Torii ◽  
...  
Keyword(s):  
Protein Import ◽  
Mitochondrial Protein ◽  
Structural Basis ◽  
Mitochondrial Protein Import ◽  
Import Receptor
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