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Schematic representation of putative interactions at the level of the inner...
Published: 17 July 2012
FIG. 1. Schematic representation of putative interactions at the level of the inner mitochondrial membrane between hyperglycemia, mitochondrial ROS generation by the electron transport chain, proton leak, and mitochondrial fission, based on available knowledge and the contribution by Galloway et al. ( 20 ). Compared with euglycemic conditions (A), hyperglycemia (B) ultimately favors both excess respiratory substrates utilization with enhanced electron transfer through the electron transport chain, and enhanced mitochondrial fission. Higher inner membrane potential is not completely utilized for ATP synthesis, may cause proton accumulation in the intermembrane space and hyperpolarization that may contribute to enhanced ROS production. As demonstrated in ref. 20 , partial inhibition of mitochondrial fission (C) may result in moderate proton leak with reduced hyperpolarization and lower mitochondrial ROS production. G, glucose; e, electron(s); ETC, electron transport chain; H+, proton(s). FIG. 1. Schematic representation of putative interactions at the level of the inner mitochondrial membrane between hyperglycemia, mitochondrial ROS generation by the electron transport chain, proton leak, and mitochondrial fission, based on available knowledge and the contribution by Galloway et al. (20). Compared with euglycemic conditions (A), hyperglycemia (B) ultimately favors both excess respiratory substrates utilization with enhanced electron transfer through the electron transport chain, and enhanced mitochondrial fission. Higher inner membrane potential is not completely utilized for ATP synthesis, may cause proton accumulation in the intermembrane space and hyperpolarization that may contribute to enhanced ROS production. As demonstrated in ref. 20, partial inhibition of mitochondrial fission (C) may result in moderate proton leak with reduced hyperpolarization and lower mitochondrial ROS production. G, glucose; e−, electron(s); ETC, electron transport chain; H+, proton(s). More
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The distribution of overall succinate oxidase activity (complex II-IV) amon...
Published: 01 January 2005
FIG. 2. The distribution of overall succinate oxidase activity (complex II-IV) among subsarcolemmal and intermyofibrillar mitochondrial (IFM) fractions, as a percentage of overall succinate oxidase activity, is shown for skeletal muscle from lean, obese, and type 2 diabetic (T2DM) research volunteers. *Lean vs. obese or type 2 diabetic subjects, P < 0.01; **type 2 diabetic vs. obese subjects, P < 0.05. ETC, electron transport chain; SSM, subsarcolemmal mitochondria. FIG. 2. The distribution of overall succinate oxidase activity (complex II-IV) among subsarcolemmal and intermyofibrillar mitochondrial (IFM) fractions, as a percentage of overall succinate oxidase activity, is shown for skeletal muscle from lean, obese, and type 2 diabetic (T2DM) research volunteers. *Lean vs. obese or type 2 diabetic subjects, P < 0.01; **type 2 diabetic vs. obese subjects, P < 0.05. ETC, electron transport chain; SSM, subsarcolemmal mitochondria. More
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Effect of metformin on expression of key lipolytic and mitochondrial protei...
Published: 13 February 2014
Figure 5 Effect of metformin on expression of key lipolytic and mitochondrial proteins in BAT. BAT was collected in control (black bars) and metformin-treated (open bars) mice, as described in Fig. 4 . The protein expression of HSL, ATGL, ADRP, eNOS, PGC-1α, and CS and of various mitochondrial respiratory chain subunits (C1, NDUFB8; C2, SDHB; C3, UQCRC2; C4, MTCO1 and COX4l1; C5, ATP5A) was assessed by Western blot (A), followed by densitometric quantification (BE). Tubulin expression was used as internal housekeeping protein. The ratio of mitochondrial respiratory chain complex 2 to complex 1 was calculated (F). Data are means ± SEM (n = 8 per group). *P < 0.05 vs. control. ETC, electron transport chain. p/T, phospho-to-total ratio. Figure 5. Effect of metformin on expression of key lipolytic and mitochondrial proteins in BAT. BAT was collected in control (black bars) and metformin-treated (open bars) mice, as described in Fig. 4. The protein expression of HSL, ATGL, ADRP, eNOS, PGC-1α, and CS and of various mitochondrial respiratory chain subunits (C1, NDUFB8; C2, SDHB; C3, UQCRC2; C4, MTCO1 and COX4l1; C5, ATP5A) was assessed by Western blot (A), followed by densitometric quantification (B–E). Tubulin expression was used as internal housekeeping protein. The ratio of mitochondrial respiratory chain complex 2 to complex 1 was calculated (F). Data are means ± SEM (n = 8 per group). *P < 0.05 vs. control. ETC, electron transport chain. p/T, phospho-to-total ratio. More
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<em>A</em>: mRNA expression of <em>degs1</em> in 3T3-L1 tre...
Published: 28 October 2014
Figure 2 A: mRNA expression of degs1 in 3T3-L1 treated with short hairpin RNA (shRNA) against degs1. B and C: Cell proliferation (XTT and BrdU assays every 24 h until 96 and 72 h, respectively). D: mRNA expression of Cdk2, Bcl2, Bax, and Caspase3. E: Apoptosis and cell death rate. F: Protein expression of Cdk2. G: Oxygen consumption rate. H: mRNA expression of antioxidant machinery genes. I: Reactive oxygen species production. J: Mitochondria levels. All these experiments were perfomed in degs1 KD and WT 3T3-L1 cells. Values are the mean ± SEM of three separate experiments performed in triplicate. ETC, electron transport chain; MFI, mean fluorescence intensity; PI, propidium iodide. *P < 0.05. Figure 2. A: mRNA expression of degs1 in 3T3-L1 treated with short hairpin RNA (shRNA) against degs1. B and C: Cell proliferation (XTT and BrdU assays every 24 h until 96 and 72 h, respectively). D: mRNA expression of Cdk2, Bcl2, Bax, and Caspase3. E: Apoptosis and cell death rate. F: Protein expression of Cdk2. G: Oxygen consumption rate. H: mRNA expression of antioxidant machinery genes. I: Reactive oxygen species production. J: Mitochondria levels. All these experiments were perfomed in degs1 KD and WT 3T3-L1 cells. Values are the mean ± SEM of three separate experiments performed in triplicate. ETC, electron transport chain; MFI, mean fluorescence intensity; PI, propidium iodide. *P < 0.05. More
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Methyl pyruvate rescues <em>Drp1</em>-related deficiency in insulin...
Published: 07 February 2017
Figure 6 Methyl pyruvate rescues Drp1-related deficiency in insulin secretion and bioenergetics in pancreatic mouse islets. A and B: Batches of eight size-matched islets were exposed to different substrates/secretagogues with or without mdivi-1. After incubation, supernatant was collected to measure insulin secretion (A) and insulin secretion normalized to basal control (B). Data are represented as means ± SEM (n = 3). C: Mitochondrial respiration. D: Proton leak respiration. ATP-linked respiration (E) and coupling efficiency (F). G: Schematic model of the impact of Drp1 during GSIS, emphasizing the rescue of insulin secretion with pyruvate. Statistical significance of mean differences was tested by unpaired two-tailed Student t test to compare two variables, and one-way ANOVA (with Bonferroni post hoc analysis) was used for multiple comparisons. *P < 0.05; **P < 0.01. ETC, electron transport chain; G, glucose; MP, methyl pyruvate. Figure 6. Methyl pyruvate rescues Drp1-related deficiency in insulin secretion and bioenergetics in pancreatic mouse islets. A and B: Batches of eight size-matched islets were exposed to different substrates/secretagogues with or without mdivi-1. After incubation, supernatant was collected to measure insulin secretion (A) and insulin secretion normalized to basal control (B). Data are represented as means ± SEM (n = 3). C: Mitochondrial respiration. D: Proton leak respiration. ATP-linked respiration (E) and coupling efficiency (F). G: Schematic model of the impact of Drp1 during GSIS, emphasizing the rescue of insulin secretion with pyruvate. Statistical significance of mean differences was tested by unpaired two-tailed Student t test to compare two variables, and one-way ANOVA (with Bonferroni post hoc analysis) was used for multiple comparisons. *P < 0.05; **P < 0.01. ETC, electron transport chain; G, glucose; MP, methyl pyruvate. More
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Hypothetical model illustrating the molecular basis of insulin-induced meta...
Published: 17 February 2015
Figure 1 Hypothetical model illustrating the molecular basis of insulin-induced metabolic stress in patients with poorly controlled T2D in which both blood glucose and FFA levels are persistently elevated. Depicted here is a cell in which (A) IR protects from nutrient overload and metabolic stress by limiting glucose flux into the cell and (B) the IR protection is overridden by a high dose of exogenous insulin therapy, which promotes excess glucose uptake and glucolipotoxicity. Excess glucose supply to the mitochondria results in reducing equivalent overload of the electron transfer chain and enhanced production of ATP and ROS, resulting in oxidative damage. The resulting increased ATP/AMP ratio inhibits AMPK, which has the effect of decreasing FFA oxidation (limiting nutrient detoxification) favoring fat deposition. Enhanced glucose uptake can also result in excessive glycogen deposition and increased activities of the toxic polyol, hexosamine, and AGE formation pathways. Glucose that is metabolized via the anaplerosis pathway can also increase cytosolic acetyl-CoA (AcCoA) and malonyl-CoA (MalCoA). AcCoA and MalCoA are then available for cholesterol and fatty acid synthesis, increasing the lipid load on the cell. MalCoA also inhibits fatty acyl-CoA (FACoA) entry into the mitochondria such that FACoA is more available for synthesis of complex lipids, including glycerolipids (phospholipids, diacylglycerols, and triglycerides) and ceramides. This can result in endoplasmic reticulum stress and the accumulation of lipid droplets (steatosis). Increased ROS production, toxic lipid accumulation, and reduced AMPK activity are factors that also activate the inflammasome contributing to cardiac injury. The overall effect is nutrient overload and metabolic stress causing cell dysfunction or death and cardiac inflammation. CD36, free fatty acid transporter; DAG, diacylglycerols; ER, endoplasmic reticulum; ETC, electron transport chain; GLUT4, facilitative glucose transporter 4; IRc, insulin receptor; MITO DYSF, mitochondrial dysfunction; OXID STRESS, oxidative stress; Pyr, pyruvate; PL, phospholipids; TG, triglycerides; Tx, treatment. Figure 1. Hypothetical model illustrating the molecular basis of insulin-induced metabolic stress in patients with poorly controlled T2D in which both blood glucose and FFA levels are persistently elevated. Depicted here is a cell in which (A) IR protects from nutrient overload and metabolic stress by limiting glucose flux into the cell and (B) the IR protection is overridden by a high dose of exogenous insulin therapy, which promotes excess glucose uptake and glucolipotoxicity. Excess glucose supply to the mitochondria results in reducing equivalent overload of the electron transfer chain and enhanced production of ATP and ROS, resulting in oxidative damage. The resulting increased ATP/AMP ratio inhibits AMPK, which has the effect of decreasing FFA oxidation (limiting nutrient detoxification) favoring fat deposition. Enhanced glucose uptake can also result in excessive glycogen deposition and increased activities of the toxic polyol, hexosamine, and AGE formation pathways. Glucose that is metabolized via the anaplerosis pathway can also increase cytosolic acetyl-CoA (AcCoA) and malonyl-CoA (MalCoA). AcCoA and MalCoA are then available for cholesterol and fatty acid synthesis, increasing the lipid load on the cell. MalCoA also inhibits fatty acyl-CoA (FACoA) entry into the mitochondria such that FACoA is more available for synthesis of complex lipids, including glycerolipids (phospholipids, diacylglycerols, and triglycerides) and ceramides. This can result in endoplasmic reticulum stress and the accumulation of lipid droplets (steatosis). Increased ROS production, toxic lipid accumulation, and reduced AMPK activity are factors that also activate the inflammasome contributing to cardiac injury. The overall effect is nutrient overload and metabolic stress causing cell dysfunction or death and cardiac inflammation. CD36, free fatty acid transporter; DAG, diacylglycerols; ER, endoplasmic reticulum; ETC, electron transport chain; GLUT4, facilitative glucose transporter 4; IRc, insulin receptor; MITO DYSF, mitochondrial dysfunction; OXID STRESS, oxidative stress; Pyr, pyruvate; PL, phospholipids; TG, triglycerides; Tx, treatment. More
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Temporal gene expression patterns during GK diabetes progression. <em>A</em>...
Published: 30 May 2017
Figure 2 Temporal gene expression patterns during GK diabetes progression. A: Pearson correlation analysis of the temporal mRNA and protein expression of 746 overlapping DE genes. In total, 76.8% of genes were positively correlated, of which 41.3% were significantly correlated (adjusted P < 0.01). The mean Pearson correlation coefficient was 0.388. B: DAVID analysis of positively correlated DE genes revealed two enriched functional annotations primarily associated with carbon metabolism and ribosomes. No functional annotation was enriched for negatively correlated DE genes. C: Time course dynamic expression clustering analysis of DE genes. First, fold changes in DE genes were transformed into z scores. Next, the k-means clustering method was used to classify the genes into 12 mRNA and 9 protein patterns, displayed as a Circos figure. Functional enrichment analyses of the genes within each pattern were carried out by using EnrichmentMap software. The enriched GO functional groups are selectively highlighted with transparent pink (upregulated) and blue (downregulated) circles. ER, endoplasmic reticulum; ETC, electron transport chain; FA, fatty acid; IKK, IκB kinase; MAPKKK, mitogen-activated protein kinase kinase kinase; w, week. Figure 2. Temporal gene expression patterns during GK diabetes progression. A: Pearson correlation analysis of the temporal mRNA and protein expression of 746 overlapping DE genes. In total, 76.8% of genes were positively correlated, of which 41.3% were significantly correlated (adjusted P < 0.01). The mean Pearson correlation coefficient was 0.388. B: DAVID analysis of positively correlated DE genes revealed two enriched functional annotations primarily associated with carbon metabolism and ribosomes. No functional annotation was enriched for negatively correlated DE genes. C: Time course dynamic expression clustering analysis of DE genes. First, fold changes in DE genes were transformed into z scores. Next, the k-means clustering method was used to classify the genes into 12 mRNA and 9 protein patterns, displayed as a Circos figure. Functional enrichment analyses of the genes within each pattern were carried out by using EnrichmentMap software. The enriched GO functional groups are selectively highlighted with transparent pink (upregulated) and blue (downregulated) circles. ER, endoplasmic reticulum; ETC, electron transport chain; FA, fatty acid; IKK, IκB kinase; MAPKKK, mitogen-activated protein kinase kinase kinase; w, week. More
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Stress recovery increases metabolic demand in human β-cells. <em>A</em>...
Published: 27 June 2018
Figure 7 Stress recovery increases metabolic demand in human β-cells. A: Heat map of significantly expressed genes between the INShiUPRlo and INSloUPRhi branches. The genes are involved in glycolysis, lactate production, pentose phosphate pathway, or tricarboxylic acid (TCA) cycle. B: Complexes of electron transport chain (ETC) are presented as individual clusters. C: Working model summarizing the findings presented in A and B. Figure 7. Stress recovery increases metabolic demand in human β-cells. A: Heat map of significantly expressed genes between the INShiUPRlo and INSloUPRhi branches. The genes are involved in glycolysis, lactate production, pentose phosphate pathway, or tricarboxylic acid (TCA) cycle. B: Complexes of electron transport chain (ETC) are presented as individual clusters. C: Working model summarizing the findings presented in A and B. More
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Results of analysis of manually curated protein sets for complexes I–V of t...
Published: 15 October 2009
FIG. 5. Results of analysis of manually curated protein sets for complexes I–V of the electron transport chain (ETC). Data are given as means ± SE scaled NSAF values for lean control (□), obese nondiabetic ( ), and type 2 diabetic participants (■). *P < 0.05, **P < 0.01 vs. lean control subjects (see research design and methods for details). FIG. 5. Results of analysis of manually curated protein sets for complexes I–V of the electron transport chain (ETC). Data are given as means ± SE scaled NSAF values for lean control (□), obese nondiabetic (), and type 2 diabetic participants (■). *P < 0.05, **P < 0.01 vs. lean control subjects (see research design and methods for details). More
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Results of analysis of manually curated protein sets for complexes I–V of t...
Published: 15 October 2009
FIG. 5. Results of analysis of manually curated protein sets for complexes I–V of the electron transport chain (ETC). Data are given as means ± SE scaled NSAF values for lean control (□), obese nondiabetic ( ), and type 2 diabetic participants (■). *P < 0.05, **P < 0.01 vs. lean control subjects (see research design and methods for details). FIG. 5. Results of analysis of manually curated protein sets for complexes I–V of the electron transport chain (ETC). Data are given as means ± SE scaled NSAF values for lean control (□), obese nondiabetic (), and type 2 diabetic participants (■). *P < 0.05, **P < 0.01 vs. lean control subjects (see research design and methods for details). More
Journal Articles
Journal: Diabetes
Diabetes 2008;57(4):987–994
Published: 01 April 2008
... of diet (n = 7) or diet plus exercise (n = 9). Insulin sensitivity was measured using euglycemic clamps. Mitochondria were examined in muscle biopsies before and after intervention. We measured mitochondrial content and size by electron microscopy, electron transport chain (ETC) activity...
Journal Articles
Journal: Diabetes
Diabetes 2007;56(6):1592–1599
Published: 01 June 2007
... in isolated mitochondria. Respiration was normalized to citrate synthase activity (mitochondrial content) in isolated mitochondria. Maximal ADP-stimulated respiration (state 3) with pyruvate plus malate and respiration through the electron transport chain (ETC) were reduced in type 2 diabetic patients...
Journal Articles
Journal: Diabetes
Diabetes 2021;70(5):1130–1144
Published: 01 February 2021
... CKD. Here, using next-generation sequencing, we first report significant downregulation in transcriptional networks governing oxidative phosphorylation, coupled electron transport, electron transport chain (ETC) complex assembly, and mitochondrial organization in both middle- and late-stage CKD...
Journal Articles
Journal: Diabetes
Diabetes 2012;61(8):1915–1917
Published: 17 July 2012
... hyperpolarization and lower mitochondrial ROS production. G, glucose; e, electron(s); ETC, electron transport chain; H+, proton(s). FIG. 1. Schematic representation of putative interactions at the level of the inner mitochondrial membrane between hyperglycemia, mitochondrial ROS generation...
Journal Articles
Journal: Diabetes
Diabetes 2012;61(8):2074–2083
Published: 17 July 2012
... and pyruvate-supported ROS production is unchanged. Oxidation of substrates that donate electrons at specific sites in the electron transport chain (ETC) is unchanged. The increased maximal production of ROS with fatty acid oxidation is not affected by limiting the electron flow from complex I into complex III...
Meeting Abstracts
Journal: Diabetes
Diabetes 2018;67(Supplement_1):241-OR
Published: 01 July 2018
... enzyme activities. Malonyl-lysine (Kmal) targets and inhibits glycolysis and beta-oxidation enzymes. Recently, formation of Kmal was suggested to act as a sink for mitochondrial malate, preventing its inhibition of succinate dehydrogenase in the electron transport chain (ETC). Using the db/db T2DM mouse...
Meeting Abstracts
Journal: Diabetes
Diabetes 2020;69(Supplement_1):1703-P
Published: 01 June 2020
... white and beige adipogenic differentiation. UCP-1 level was evaluated by RT-PCR and Western blot. Expression of lipid metabolism and electron transport chain (ETC) genes were analyzed by RT-PCR. ROS production was evaluated by fluorescent microscopy. Results: UCP-1 expression was decreased in beige...
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Model for the role of Sirt3 in control of skeletal muscle substrate metabol...
Published: 17 September 2013
FIG. 7. Model for the role of Sirt3 in control of skeletal muscle substrate metabolism. Sirt3 regulates PDH E1α subunit deacetylation and activates PDH activity. A: In the fed state, Sirt3 skeletal muscle expression is abundant and leads to deacetylation of PDH E1α. This is associated with dephosphorylation of PDH allowing for maximal enzyme activation, enhanced glucose utilization, and increased flux of pyruvate to acetyl-CoA used by the tricarboxylic acid (TCA) cycle and electron transport chain (ETC) to generate ATP. B: In contrast, decreased Sirt3 expression in muscle by fasting or genetic deletion leads to PDH E1α hyperacetylation and decreased PDH complex activity, which is correlated with increased PDH E1α phosphorylation in vivo. The activity of PDH controls the substrate influx to the TCA cycle from glycolysis. In the case of Sirt3 deletion, inactivation of the PDH caused by hyperacetylation leads to metabolic inflexibility as evidenced by an inability to fully oxidize glucose, a shunt of excess pyruvate toward lactate production, and increased lipid oxidation even in the fed state. CPT, carnitine palmitoyl transferase; FFA, free fatty acid; Mito, mitochondrial; OxPhos, oxidative phosphorylation. FIG. 7. Model for the role of Sirt3 in control of skeletal muscle substrate metabolism. Sirt3 regulates PDH E1α subunit deacetylation and activates PDH activity. A: In the fed state, Sirt3 skeletal muscle expression is abundant and leads to deacetylation of PDH E1α. This is associated with dephosphorylation of PDH allowing for maximal enzyme activation, enhanced glucose utilization, and increased flux of pyruvate to acetyl-CoA used by the tricarboxylic acid (TCA) cycle and electron transport chain (ETC) to generate ATP. B: In contrast, decreased Sirt3 expression in muscle by fasting or genetic deletion leads to PDH E1α hyperacetylation and decreased PDH complex activity, which is correlated with increased PDH E1α phosphorylation in vivo. The activity of PDH controls the substrate influx to the TCA cycle from glycolysis. In the case of Sirt3 deletion, inactivation of the PDH caused by hyperacetylation leads to metabolic inflexibility as evidenced by an inability to fully oxidize glucose, a shunt of excess pyruvate toward lactate production, and increased lipid oxidation even in the fed state. CPT, carnitine palmitoyl transferase; FFA, free fatty acid; Mito, mitochondrial; OxPhos, oxidative phosphorylation. More
Journal Articles
Journal: Diabetes
Diabetes db210834
Published: 26 April 2022
... (SDH) is a key mitochondrial enzyme with dual functions in the TCA cycle and electron transport chain (ETC). Using human diabetic samples and a mouse model of β-cell-specific SDH ablation (SDHBβKO), we define SDH deficiency as a driver of mitochondrial dysfunction in β-cell failure...
Meeting Abstracts
Journal: Diabetes
Diabetes 2018;67(Supplement_1):2442-PUB
Published: 01 July 2018
... decarboxylase (UROD). The lower production of heme by glucagon impaired the integrity of electron transport chain (ETC), reducing the heme-dependent complex III (Uqcrc1) and complex IV (mt-Co1). Furthermore, glucagon downregulated mitochondrial transcription factor A (TFAM) and nuclear transcription factors 1...