Early mitochondrial dysfunction in glycolytic muscle, but not oxidative muscle, of the fructose-fed insulin-resistant rat

Although evidence that type 2 diabetes mellitus (T2DM) is accompanied by mitochondrial dysfunction in skeletal muscle has been accumulating, a causal link between mitochondrial dysfunction and the pathogenesis of the disease remains unclear. Our study focuses on an early stage of the disease to determine whether mitochondrial dysfunction contributes to the development of T2DM. The fructose-fed (FF) rat was used as an animal model of early T2DM. Mitochondrial respiration and acylcarnitine species were measured in oxidative (soleus) and glycolytic [extensor digitorum longus (EDL)] muscle. Although FF rats displayed characteristic signs of T2DM, including hyperglycemia, hyperinsulinemia, and hypertriglyceridemia, mitochondrial content was preserved in both muscles from FF rats. The EDL muscle had reduced complex I and complex I and II respiration in the presence of pyruvate but not glutamate. The decrease in pyruvate-supported respiration was due to a decrease in pyruvate dehydrogenase activity. Accumulation of C14:1 and C14:2 acylcarnitine species and a decrease in respiration supported by long-chain acylcarnitines but not acetylcarnitine indicated dysfunctional β-oxidation in the EDL muscle. In contrast, the soleus muscle showed preserved mitochondrial respiration, pyruvate dehydrogenase activity, and increased fatty acid oxidation, as evidenced by overall reduced acylcarnitine levels. Aconitase activity, a sensitive index of reactive oxygen species production in mitochondria, was reduced exclusively in EDL muscle, which showed lower levels of the antioxidant enzymes thioredoxin reductase and glutathione peroxidase. Here, we show that the glycolytic EDL muscle is more prone to an imbalance between energy supply and oxidation caused by insulin resistance than the oxidative soleus muscle.

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Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Statin Toxicity

International Journal of Molecular Sciences ◽

10.3390/ijms22010424 ◽

2021 ◽

Vol 22 (1) ◽

pp. 424

Author(s):

Vlad F. Avram ◽

Imen Chamkha ◽

Eleonor Åsander-Frostner ◽

Johannes K. Ehinger ◽

Romulus Z. Timar ◽

...

Keyword(s):

Oxygen Consumption ◽

Mitochondrial Dysfunction ◽

Mitochondrial Respiration ◽

Complex I ◽

Ex Vivo ◽

Coupling Efficiency ◽

Human Platelets ◽

Lipid Lowering ◽

Lipid Lowering Therapy ◽

Cellular Models

Statins are the cornerstone of lipid-lowering therapy. Although generally well tolerated, statin-associated muscle symptoms (SAMS) represent the main reason for treatment discontinuation. Mitochondrial dysfunction of complex I has been implicated in the pathophysiology of SAMS. The present study proposed to assess the concentration-dependent ex vivo effects of three statins on mitochondrial respiration in viable human platelets and to investigate whether a cell-permeable prodrug of succinate (complex II substrate) can compensate for statin-induced mitochondrial dysfunction. Mitochondrial respiration was assessed by high-resolution respirometry in human platelets, acutely exposed to statins in the presence/absence of the prodrug NV118. Statins concentration-dependently inhibited mitochondrial respiration in both intact and permeabilized cells. Further, statins caused an increase in non-ATP generating oxygen consumption (uncoupling), severely limiting the OXPHOS coupling efficiency, a measure of the ATP generating capacity. Cerivastatin (commercially withdrawn due to muscle toxicity) displayed a similar inhibitory capacity compared with the widely prescribed and tolerable atorvastatin, but did not elicit direct complex I inhibition. NV118 increased succinate-supported mitochondrial oxygen consumption in atorvastatin/cerivastatin-exposed platelets leading to normalization of coupled (ATP generating) respiration. The results acquired in isolated human platelets were validated in a limited set of experiments using atorvastatin in HepG2 cells, reinforcing the generalizability of the findings.

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Tissue-specific control of mitochondrial respiration in obesity-related insulin resistance and diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00159.2011 ◽

2012 ◽

Vol 302 (6) ◽

pp. E731-E739 ◽

Cited By ~ 81

Author(s):

Maria H. Holmström ◽

Eduardo Iglesias-Gutierrez ◽

Juleen R. Zierath ◽

Pablo M. Garcia-Roves

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Mitochondrial Dysfunction ◽

Mitochondrial Respiration ◽

Mitochondrial Dynamics ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Respiratory Capacity ◽

Tissue Specific ◽

Mitochondrial Respiratory

The tissue-specific role of mitochondrial respiratory capacity in the development of insulin resistance and type 2 diabetes is unclear. We determined mitochondrial function in glycolytic and oxidative skeletal muscle and liver from lean (+/ ?) and obese diabetic ( db/db) mice. In lean mice, the mitochondrial respiration pattern differed between tissues. Tissue-specific mitochondrial profiles were then compared between lean and db/db mice. In liver, mitochondrial respiratory capacity and protein expression, including peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), was decreased in db/db mice, consistent with increased mitochondrial fission. In glycolytic muscle, mitochondrial respiration, as well as protein and mRNA expression of mitochondrial markers, was increased in db/db mice, suggesting increased mitochondrial content and fatty acid oxidation capacity. In oxidative muscle, mitochondrial complex I function and PGC-1α and mitochondrial transcription factor A (TFAM) protein levels were decreased in db/db mice, along with increased level of proteins related to mitochondrial dynamics. In conclusion, mitochondrial respiratory performance is under the control of tissue-specific mechanisms and is not uniformly altered in response to obesity. Furthermore, insulin resistance in glycolytic skeletal muscle can be maintained by a mechanism independent of mitochondrial dysfunction. Conversely, insulin resistance in liver and oxidative skeletal muscle from db/db mice is coincident with mitochondrial dysfunction.

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Effect of Pyruvate on Pyruvate Dehydrogenase Activity and Fatty Acid Oxidation in Rat Fat-Cells

Biochemical Society Transactions ◽

10.1042/bst0050989 ◽

1977 ◽

Vol 5 (4) ◽

pp. 989-992

Author(s):

S. R. SOORANNA ◽

R. D. HARPER ◽

E. D. SAGGERSON

Keyword(s):

Fatty Acid ◽

Dehydrogenase Activity ◽

Fatty Acid Oxidation ◽

Pyruvate Dehydrogenase ◽

Acid Oxidation ◽

Fat Cells ◽

Rat Fat Cells

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Gut-Derived Metabolite Indole-3-Propionic Acid Modulates Mitochondrial Function in Cardiomyocytes and Alters Cardiac Function

Frontiers in Medicine ◽

10.3389/fmed.2021.648259 ◽

2021 ◽

Vol 8 ◽

Author(s):

Maren Gesper ◽

Alena B. H. Nonnast ◽

Nina Kumowski ◽

Robert Stoehr ◽

Katharina Schuett ◽

...

Keyword(s):

Heart Failure ◽

Endothelial Cells ◽

Fatty Acid ◽

Cardiac Function ◽

Mitochondrial Dysfunction ◽

Propionic Acid ◽

Mitochondrial Function ◽

Mitochondrial Respiration ◽

Acid Oxidation ◽

Microbial Metabolites

Background: The gut microbiome has been linked to the onset of cardiometabolic diseases, in part facilitated through gut microbiota-dependent metabolites such as trimethylamine-N-oxide. However, molecular pathways associated to heart failure mediated by microbial metabolites remain largely elusive. Mitochondria play a pivotal role in cellular energy metabolism and mitochondrial dysfunction has been associated to heart failure pathogenesis. Aim of the current study was to evaluate the impact of gut-derived metabolites on mitochondrial function in cardiomyocytes via an in vitro screening approach.Methods: Based on a systematic Medline research, 25 microbial metabolites were identified and screened for their metabolic impact with a focus on mitochondrial respiration in HL-1 cardiomyocytes. Oxygen consumption rate in response to different modulators of the respiratory chain were measured by a live-cell metabolic assay platform. For one of the identified metabolites, indole-3-propionic acid, studies on specific mitochondrial complexes, cytochrome c, fatty acid oxidation, mitochondrial membrane potential, and reactive oxygen species production were performed. Mitochondrial function in response to this metabolite was further tested in human hepatic and endothelial cells. Additionally, the effect of indole-3-propionic acid on cardiac function was studied in isolated perfused hearts of C57BL/6J mice.Results: Among the metabolites examined, microbial tryptophan derivative indole-3-propionic acid could be identified as a modulator of mitochondrial function in cardiomyocytes. While acute treatment induced enhancement of maximal mitochondrial respiration (+21.5 ± 7.8%, p < 0.05), chronic exposure led to mitochondrial dysfunction (−18.9 ± 9.1%; p < 0.001) in cardiomyocytes. The latter effect of indole-3-propionic acids could also be observed in human hepatic and endothelial cells. In isolated perfused mouse hearts, indole-3-propionic acid was dose-dependently able to improve cardiac contractility from +26.8 ± 11.6% (p < 0.05) at 1 μM up to +93.6 ± 14.4% (p < 0.001) at 100 μM. Our mechanistic studies on indole-3-propionic acids suggest potential involvement of fatty acid oxidation in HL-1 cardiomyocytes.Conclusion: Our data indicate a direct impact of microbial metabolites on cardiac physiology. Gut-derived metabolite indole-3-propionic acid was identified as mitochondrial modulator in cardiomyocytes and altered cardiac function in an ex vivo mouse model.

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Pronounced α-synuclein pathology in a seeding-based mouse model is not sufficient to induce mitochondrial respiration deficits in the striatum and amygdala

10.1101/2020.03.26.006189 ◽

2020 ◽

Author(s):

Johannes Burtscher ◽

Jean-Christophe Copin ◽

Carmen Sandi ◽

Hilal A. Lashuel

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Mitochondrial Dysfunction ◽

Mitochondrial Respiration ◽

Early Stage ◽

Relevant Literature ◽

Brain Regions ◽

Substantia Nigra Pars Compacta ◽

Ros Generation

AbstractIncreasing evidence suggests that crosstalk between α-synuclein pathology formation and mitochondrial dysfunctions plays a central role in the pathogenesis of Parkinson’s disease and related synucleinopathies. While mitochondrial dysfunction is a well-studied phenomenon in the substantia nigra, which is selectively vulnerable in Parkinson’s disease and some models thereof, less information is available in other brain regions that are also affected by synuclein pathology.Therefore, we sought to test the hypothesis that early α-synuclein pathology causes mitochondrial dysfunction, and that this effect might be exacerbated in conditions of increased vulnerability of affected brain regions, such as the amygdala.We combined a model of intracerebral α-synuclein pathology seeding with chronic glucocorticoid treatment modelling non-motor symptoms of Parkinson’s disease and affecting amygdala physiology. We measured mitochondrial respiration, ROS generation and protein abundance as well as α-synuclein pathology in male mice.Chronic corticosterone administration induced mitochondrial hyperactivity in the amygdala. Although injection of α-synuclein preformed fibrils into the striatum resulted in pronounced α-synuclein pathology in both striatum and amygdala, mitochondrial respiration in these brain regions was altered in neither chronic corticosterone nor control conditions.Our results suggest that early stage α-synuclein pathology does not influence mitochondrial respiration in the striatum and amygdala, even in corticosterone-induced respirational hyperactivity. We discuss our findings in light of relevant literature, warn of a potential publication bias and encourage scientist to report their negative results in the frame of this model.Significance statementWe provide evidence that early stage synucleinopathy by itself or in combination with exogenous corticosterone induced amygdala hyperactivity did not compromise mitochondrial respiration in the striatum and amygdala in one of the most commonly used models of synucleinopathies. These results may explain, why this model in the hands of many research groups does not elicit pronounced Parkinson’s disease like symptoms in the absence of mitochondrial dysfunction in brain regions strongly affected by synuclein pathology and involved in non-motor (amygdala) and motor (striatum) symptoms. Our findings call for rigorous investigation of the short- and long-term effects of α-synuclein pathology on mitochondrial function/dysfunction in this model, in particular in brain regions strongly affected by neurodegeneration such as the substantia nigra pars compacta.

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11β-HSD1 reduces metabolic efficacy and adiponectin synthesis in hypertrophic adipocytes

Journal of Endocrinology ◽

10.1530/joe-15-0117 ◽

2015 ◽

Vol 225 (3) ◽

pp. 147-158 ◽

Cited By ~ 5

Author(s):

Eun Hee Koh ◽

Ah-Ram Kim ◽

Hyunshik Kim ◽

Jin Hee Kim ◽

Hye-Sun Park ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Mrna Expression ◽

Mitochondrial Biogenesis ◽

Mitochondrial Respiration ◽

Gastric Lavage ◽

Acid Oxidation ◽

Long Duration ◽

Plasma Adiponectin Level ◽

Adipocyte Hypertrophy

Mitochondrial dysfunction in hypertrophic adipocytes can reduce adiponectin synthesis. We investigated whether 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) expression is increased in hypertrophic adipocytes and whether this is responsible for mitochondrial dysfunction and reduced adiponectin synthesis. Differentiated 3T3L1 adipocytes were cultured for up to 21 days. The effect of AZD6925, a selective 11β-HSD1 inhibitor, on metabolism was examined. db/db mice were administered 600 mg/kg AZD6925 daily for 4 weeks via gastric lavage. Mitochondrial DNA (mtDNA) content, mRNA expression levels of 11β-Hsd1 and mitochondrial biogenesis factors, adiponectin synthesis, fatty acid oxidation (FAO), oxygen consumption rate and glycolysis were measured. Adipocyte hypertrophy in 3T3L1 cells exposed to a long duration of culture was associated with increased 11β-Hsd1 mRNA expression and reduced mtDNA content, mitochondrial biogenesis factor expression and adiponectin synthesis. These cells displayed reduced mitochondrial respiration and increased glycolysis. Treatment of these cells with AZD6925 increased adiponectin synthesis and mitochondrial respiration. Inhibition of FAO by etomoxir blocked the AZD6925-induced increase in adiponectin synthesis, indicating that 11β-HSD1-mediated reductions in FAO are responsible for the reduction in adiponectin synthesis. The expression level of 11β-Hsd1 was higher in adipose tissues of db/db mice. Administration of AZD6925 to db/db mice increased the plasma adiponectin level and adipose tissue FAO. In conclusion, increased 11β-HSD1 expression contributes to reduced mitochondrial respiration and adiponectin synthesis in hypertrophic adipocytes.

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Effect of thyroxine treatment on exogenous myocardial lactate oxidation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1982.243.5.h722 ◽

1982 ◽

Vol 243 (5) ◽

pp. H722-H728

Author(s):

M. Fintel ◽

A. H. Burns

Keyword(s):

Fatty Acids ◽

Free Fatty Acids ◽

Dehydrogenase Activity ◽

Pyruvate Dehydrogenase ◽

Acid Oxidation ◽

Lactate Oxidation ◽

Thyroxine Treatment ◽

Heart Preparation ◽

Mitochondrial Oxidation ◽

Working Rat Heart

The effect of thyroxine treatment on myocardial lactate oxidation was examined by use of an isolated, working rat heart preparation. Thyroxine treatment, both acute and chronic, was associated with a decrease in lactate oxidation, when the heart was perfused with a physiological blend of substrates (free fatty acids, lactate, and glucose). This decrease in lactate oxidation was not caused by a generalized impairment in mitochondrial oxidation of acetyl coenzyme A (CoA), as oxygen consumption was normal and fatty acid oxidation was elevated in the treated animals. The block in lactate oxidation was localized to the conversion of pyruvate to acetyl CoA, as indicated by the depressed oxidation of pyruvate and lactate. Thyroxine treatment was associated with a decrease in pyruvate dehydrogenase activity. The decrease in pyruvate dehydrogenase activity was reversible and was attributed to the enhanced myocardial oxidation of free fatty acids.

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