Substrate regulation of mitochondrial oxidative phosphorylation in hypercapnic rabbit muscle

1992 ◽  
Vol 72 (2) ◽  
pp. 521-528 ◽  
Author(s):  
S. Nioka ◽  
Z. Argov ◽  
G. P. Dobson ◽  
R. E. Forster ◽  
H. V. Subramanian ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Intracellular Ph ◽  
Isometric Tension ◽  
Muscle Performance ◽  
Oxidative Enzymes ◽  
Rabbit Muscle ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Atp Production

Endurance muscle performance is highly dependent on ATP production from mitochondrial oxidative phosphorylation. To study the role of the mitochondrial oxidative enzymes in muscle fatigue, we analyzed the relationship between the concentrations of substrates associated with ATP synthesis and the muscle performance of electrically stimulated rabbit muscle under CO2-induced acidosis. Two different conditions of pacing-induced muscle performance were produced in the gastrocnemius and soleus muscle groups in anesthetized rabbits by stimulating the sciatic nerve submaximally at two frequencies. Phosphorus nuclear magnetic resonance was used to measure ATP, phosphocreatine, and Pi and to provide data for a calculation of intracellular pH and free ADP. To induce acidosis, the animal was ventilated with 20% CO2. The administration of CO2 effectively reduced the intracellular pH from 6.9 to 6.7 and reduced the isometric tension-time integral (TTI) to below half the value measured in normocapnia at the low pacing frequency. A twofold increase in the pacing frequency resulted in a doubling of the TTI in normocapnia and a tripling of TTI in hypercapnia. The increases in TTI corresponded with increases in free ADP and Pi concentrations. Under the various conditions, all free ADP values were near the in vitro Michaelis-Menten constant (Km) of ADP. The Michaelis-Menten relationship of the oxidative phosphorylative enzymes was applied to the change in substrate concentrations with respect to TTI. From this relationship we observed that the in vivo Km of free ADP was 26 microM, which is close to the in nitro Km, and that Km and maximal reaction velocity did not change under hypercapnia and increased pacing frequency.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Let-7a regulates EV secretion and mitochondrial oxidative phosphorylation by targeting SNAP23 in colorectal cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
You Dong Liu ◽  
Xiao Peng Zhuang ◽  
Dong Lan Cai ◽  
Can Cao ◽  
Qi Sheng Gu ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Metabolic Reprogramming ◽  
Luciferase Reporter ◽  
Mitochondrial Oxidative Phosphorylation ◽  
In Vivo Assays ◽  
Reporter Assays ◽  
Extracellular Mirna

Abstract Background MicroRNAs (miRNAs) are abundant in tumor-derived extracellular vesicles (EVs) and the functions of extracellular miRNA to recipient cells have been extensively studied with tumorigenesis. However, the role of miRNA in EV secretion from cancer cells remains unknown. Methods qPCR and bioinformatics analysis were applied for determining extracellular let-7a expression from CRC patient serum and cells. Nanosight particle tracking analysis was performed for investigating the effect of let-7a on EV secretion. Luciferase reporter assays was used for identifying targeted genes synaptosome-associated protein 23 (SNAP23). In vitro and in vivo assays were used for exploring the function of let-7a/SNAP23 axis in CRC progression. Bioenergetic assays were performed for investigating the role of let-7a/SNAP23 in cellular metabolic reprogramming. Results let-7a miRNA was elevated in serum EVs from CRC patients and was enriched in CRC cell-derived EVs. We determined that let-7a could suppress EV secretion directly targeting SNAP23. In turn, SNAP23 promotes EV secretion of let-7a to downregulate the intracellular let-7a expression. In addition, we found a novel mechanism of let-7a/SNAP23 axis by regulating mitochondrial oxidative phosphorylation (OXPHOS) through Lin28a/SDHA signaling pathway. Conclusions Let-7a plays an essential role in not only inhibiting EV secretion, but also suppressing OXPHOS through SNAP23, resulting in the suppression of CRC progression, suggesting that let-7a/SNAP23 axis could provide not only effective tumor biomarkers but also novel targets for tumor therapeutic strategies.

scholarly journals Skeletal muscle mitochondrial oxidative phosphorylation function in idiopathic pulmonary arterial hypertension: in vivo and in vitro study

2018 ◽  
Vol 8 (2) ◽  
pp. 204589401876829 ◽  
Author(s):  
Sasiharan Sithamparanathan ◽  
Mariana C. Rocha ◽  
Jehill D. Parikh ◽  
Karolina A. Rygiel ◽  
Gavin Falkous ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Oxidative Phosphorylation ◽  
Arterial Hypertension ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Pulmonary Vessels ◽  
Pulmonary Arterial

Mitochondrial dysfunction within the pulmonary vessels has been shown to contribute to the pathology of idiopathic pulmonary arterial hypertension (IPAH). We investigated the hypothesis of whether impaired exercise capacity observed in IPAH patients is in part due to primary mitochondrial oxidative phosphorylation (OXPHOS) dysfunction in skeletal muscle. This could lead to potentially new avenues of treatment beyond targeting the pulmonary vessels. Nine clinically stable participants with IPAH underwent cardiopulmonary exercise testing, in vivo and in vitro assessment of mitochondrial function by 31P-magnetic resonance spectroscopy (31P-MRS) and laboratory muscle biopsy analysis. 31P-MRS showed abnormal skeletal muscle bioenergetics with prolonged recovery times of phosphocreatine and abnormal muscle pH handling. Histochemistry and quadruple immunofluorescence performed on muscle biopsies showed normal function and subunit protein abundance of the complexes within the OXPHOS system. Our findings suggest that there is no primary mitochondrial OXPHOS dysfunction but raises the possibility of impaired oxygen delivery to the mitochondria affecting skeletal muscle bioenergetics during exercise.

scholarly journals Oxidative phosphorylation is required for powering motility and development of the sleeping sickness parasite Trypanosoma brucei within the tsetse fly vector

2021 ◽  
Author(s):  
Caroline E Dewar ◽  
Aitor Casas-Sánchez ◽  
Constentin Dieme ◽  
Aline Crouzols ◽  
Lee Haines ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Trypanosoma Brucei ◽  
Atp Synthase ◽  
Sleeping Sickness ◽  
Tsetse Fly ◽  
Tsetse Flies ◽  
Respiratory Chain Complexes ◽  
Atp Production

The single-celled parasite Trypanosoma brucei causes sleeping sickness in humans and nagana in livestock and is transmitted by hematophagous tsetse flies. Lifecycle progression from mammalian bloodstream form to tsetse midgut form and, subsequently, infective salivary gland form depends on complex developmental steps and migration within different fly tissues. As the parasite colonises the glucose-poor insect midgut, its ATP production is thought to depend on activation of mitochondrial amino acid catabolism via oxidative phosphorylation. This process involves respiratory chain complexes and the F1FO-ATP synthase, and it requires protein subunits of these complexes that are encoded in the parasite's mitochondrial DNA (kinetoplast or kDNA). Here we show that a progressive loss of kDNA-encoded functions correlates with an increasingly impaired ability of T. brucei to initiate and complete its development in the tsetse. First, parasites with a mutated F1FO-ATP synthase with a reduced capacity for oxidative phosphorylation can initiate differentiation from bloodstream to insect form, but they are unable to proliferate in vitro. Unexpectedly, these cells can still colonise the tsetse midgut. However, these parasites exhibit a motility defect and are severely impaired in colonising or migrating to subsequent tsetse tissues. Second, parasites with a fully disrupted F1FO-ATP synthase complex that is completely unable to produce ATP by oxidative phosphorylation can still differentiate to the first insect stage in vitro but die within a few days and cannot establish a midgut infection in vivo. Third, mutant parasites lacking kDNA entirely can initiate differentiation but die within 24 h. Together, these three scenarios show that efficient ATP production via oxidative phosphorylation is not essential for initial colonisation of the tsetse vector, but it is required to power trypanosome migration within the fly.

scholarly journals Increased intramyocellular lipids but unaltered in vivo mitochondrial oxidative phosphorylation in skeletal muscle of adipose triglyceride lipase-deficient mice

2012 ◽  
Vol 303 (1) ◽  
pp. E71-E81 ◽  
Author(s):  
P. M. Nunes ◽  
T. van de Weijer ◽  
A. Veltien ◽  
H. Arnts ◽  
M. K. C. Hesselink ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Magnetic Resonance ◽  
Oxidative Phosphorylation ◽  
Muscle Performance ◽  
Resonance Spectroscopy ◽  
Lipolytic Enzyme ◽  
Adipose Triglyceride Lipase ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Triglyceride Lipase

Adipose triglyceride lipase (ATGL) is a lipolytic enzyme that is highly specific for triglyceride hydrolysis. The ATGL-knockout mouse (ATGL−/−) accumulates lipid droplets in various tissues, including skeletal muscle, and has poor maximal running velocity and endurance capacity. In this study, we tested whether abnormal lipid accumulation in skeletal muscle impairs mitochondrial oxidative phosphorylation, and hence, explains the poor muscle performance of ATGL−/− mice. In vivo 1H magnetic resonance spectroscopy of the tibialis anterior of ATGL−/− mice revealed that its intramyocellular lipid pool is approximately sixfold higher than in WT controls ( P = 0.0007). In skeletal muscle of ATGL−/− mice, glycogen content was decreased by 30% ( P < 0.05). In vivo 31P magnetic resonance spectra of resting muscles showed that WT and ATGL−/− mice have a similar energy status: [PCr], [Pi], PCr/ATP ratio, PCr/Pi ratio, and intracellular pH. Electrostimulated muscles from WT and ATGL−/− mice showed the same PCr depletion and pH reduction. Moreover, the monoexponential fitting of the PCr recovery curve yielded similar PCr recovery times (τPCr; 54.1 ± 6.1 s for the ATGL−/− and 58.1 ± 5.8 s for the WT), which means that overall muscular mitochondrial oxidative capacity was comparable between the genotypes. Despite similar in vivo mitochondrial oxidative capacities, the electrostimulated muscles from ATGL−/− mice displayed significantly lower force production and increased muscle relaxation time than the WT. These findings suggest that mechanisms other than mitochondrial dysfunction cause the impaired muscle performance of ATGL−/− mice.

scholarly journals TSPO deficiency induces mitochondrial dysfunction, leading to hypoxia, angiogenesis, and a growth-promoting metabolic shift toward glycolysis in glioblastoma

2019 ◽  
Author(s):  
Yi Fu ◽  
Dongdong Wang ◽  
Huaishan Wang ◽  
Menghua Cai ◽  
Chao Li ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Translocator Protein ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Diagnostic Biomarkers ◽  
Extracellular Flux ◽  
Glioma Cell Proliferation ◽  
Glioma Growth ◽  
Proliferation In Vitro

Abstract Background The ligands of mitochondrial translocator protein (TSPO) have been widely used as diagnostic biomarkers for glioma. However, the true biological actions of TSPO in vivo and its role in glioma tumorigenesis remain elusive. Methods TSPO knockout xenograft and spontaneous mouse glioma models were employed to assess the roles of TSPO in the pathogenesis of glioma. A Seahorse Extracellular Flux Analyzer was used to evaluate mitochondrial oxidative phosphorylation and glycolysis in TSPO knockout and wild-type glioma cells. Results TSPO deficiency promoted glioma cell proliferation in vitro in mouse GL261 cells and patient-derived stem cell–like GBM1B cells. TSPO knockout increased glioma growth and angiogenesis in intracranial xenografts and a mouse spontaneous glioma model. Loss of TSPO resulted in a greater number of fragmented mitochondria, increased glucose uptake and lactic acid conversion, decreased oxidative phosphorylation, and increased glycolysis. Conclusion TSPO serves as a key regulator of glioma growth and malignancy by controlling the metabolic balance between mitochondrial oxidative phosphorylation and glycolysis. 1. TSPO deficiency promotes glioma growth and angiogenesis. 2. TSPO regulates the balance between mitochondrial oxidative phosphorylation and glycolysis.

scholarly journals Cloperastine inhibits esophageal squamous cell carcinoma proliferation in vivo and in vitro by suppressing mitochondrial oxidative phosphorylation

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Bo Li ◽  
Yin Yu ◽  
Yanan Jiang ◽  
Lili Zhao ◽  
Ang Li ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Oxidative Phosphorylation ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Major Type ◽  
High Morbidity ◽  
Mitochondrial Oxidative Phosphorylation

AbstractEsophageal squamous cell carcinoma (ESCC) is a major type of esophageal cancer. The prognosis of patients with ESCC remains poor because of the high morbidity and mortality of the disease. One strategy for drug discovery for ESCC treatment or prevention is screening FDA-approved drugs. In the present study, we found that the antitussive agent cloperastine can inhibit the proliferation of ESCC cells. However, the underlying mechanism was unclear. To determine the mechanism of this inhibitory effect, we performed proteomic analysis using KYSE150 cells treated with cloperastine and DMSO. The results identified several down-regulated signaling pathways included those of three key proteins (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex 1, NADH ubiquinone oxidoreductase subunit S5, and cytochrome C oxidase subunit 6B1) involved in oxidative phosphorylation. Meanwhile, we observed that oxidative phosphorylation in mitochondria was inhibited by the drug. Importantly, cloperastine suppressed ESCC growth in a xenograft mouse model in vivo. Our findings revealed that cloperastine inhibits the proliferation of ESCC in vivo and in vitro by suppressing mitochondrial oxidative phosphorylation.

scholarly journals Enantiomers of flurbiprofen can distinguish key pathophysiological steps of NSAID enteropathy in the rat

Gut ◽  
1998 ◽  
Vol 43 (6) ◽  
pp. 775-782 ◽  
Author(s):  
T Mahmud ◽  
S Somasundaram ◽  
G Sigthorsson ◽  
R J Simpson ◽  
S Rafi ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Intestinal Permeability ◽  
Racemic Mixture ◽  
Mitochondrial Morphology ◽  
Intestinal Damage ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Nsaid Enteropathy ◽  
Small Intestinal

Background—Non-steroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal damage by a non-prostaglandin (PG) dependent “topical” action and by inhibiting cyclooxygenase.Aims—To discriminate between these two effects by studying some key pathophysiological steps in NSAID enteropathy following administration of (R)- and (S)-flurbiprofen, the racemic mixture, and an uncoupler, dinitrophenol.Methods—The effects of dinitrophenol, racemic, (R)-, and (S)-flurbiprofen on mitochondria were assessed in vitro and on key pathophysiological features of small intestinal damage in vivo (ultrastructure by electron microscopy, mucosal prostanoid concentrations, intestinal permeability, inflammation, and ulcer count) in rats.Results—All the drugs uncoupled mitochondrial oxidative phosphorylation in vitro, caused mitochondrial damage in vivo, and increased intestinal permeability. Dinitrophenol and (R)-flurbiprofen caused no significant decreases in mucosal prostanoid concentrations (apart from a decrease in thromboxane (TX) B2 concentrations following (R)-flurbiprofen) while racemic and (S)- flurbiprofen reduced mucosal prostanoids significantly (PGE, TXB2, and 6-keto-PGF1α concentrations by 73–95%). Intestinal inflammation was significantly greater following administration of (S)-flurbiprofen and racemate than with dinitrophenol and (R)-flurbiprofen. No small intestinal ulcers were found following dinitrophenol or (R)-flurbiprofen while both racemic and (S)-flurbiprofen caused numerous ulcers.Conclusions—Dinitrophenol and (R)-flurbiprofen show similarities in their actions to uncouple mitochondrial oxidative phosphorylation in vitro, alter mitochondrial morphology in vivo, increase intestinal permeability, and cause mild inflammation without ulcers. Concurrent severe decreases in mucosal prostanoids seem to be the driving force for the development of severe inflammation and ulcers.

Influence of aldosterone on isometric tension development in the rat heart

1963 ◽  
Vol 204 (6) ◽  
pp. 1001-1004 ◽  
Author(s):  
William C. Ullrick ◽  
Robert L. Hazelwood
Keyword(s):  
Heart Muscle ◽  
Rat Heart ◽  
Isolated Rat Heart ◽  
Isometric Tension ◽  
Muscle Performance ◽  
Tension Development ◽  
Tension Time ◽  
Isometric Twitch

Isometric twitch curves were recorded from preparations of rat heart trabeculae carneae removed from normal or adrenalectomized animals, or from normal animals injected for 3 days with saline or with 3 µg/day of d-aldosterone. Preparations from normal and from adrenalectomized animals were stimulated for 60 min in aldosterone-free Ringer's solution, or for 30 min in aldosterone-free Ringer's followed by 30 min in Ringer's containing 3 x 10–4 µg/ml of d-aldosterone. For a number of preparations from adrenalectomized animals the concentration of aldosterone was increased to 3 x 10–1 µg/ml. Regardless of treatment, all preparations were stimulated for a total of 1 hr at a rate of approximately 395/min; subsequently the recorded twitch curves were analyzed for peak tension development and for tension-time area. Although adrenalectomy tended to lower these variables of in vitro heart muscle performance, aldosterone, either administered in vivo or added directly to the isolated muscle bath, was without influence. It is concluded that aldosterone in the concentrations used does not alter the isometric tension characteristics of isolated rat heart muscle.

Impairment of mitochondrial oxidative phosphorylation in skin fibroblasts of SALS and FALS patients is rescued by in vitro treatment with ROS scavengers

2021 ◽  
Vol 339 ◽  
pp. 113620
Author(s):  
Grazyna Debska-Vielhaber ◽  
Irina Miller ◽  
Viktoriya Peeva ◽  
Werner Zuschratter ◽  
Jaroslaw Walczak ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Skin Fibroblasts ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Ros Scavengers ◽  
In Vitro Treatment

scholarly journals The Role of Herbal Bioactive Components in Mitochondria Function and Cancer Therapy

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Fangfang Tao ◽  
Yanrong Zhang ◽  
Zhiqian Zhang
Keyword(s):  
Cancer Therapy ◽  
Cancer Cell ◽  
Apoptotic Cell ◽  
Redox Status ◽  
Cancer Therapies ◽  
Bioactive Components ◽  
Atp Production

Mitochondria are highly dynamic double-membrane organelles which play a well-recognized role in ATP production, calcium homeostasis, oxidation-reduction (redox) status, apoptotic cell death, and inflammation. Dysfunction of mitochondria has long been observed in a number of human diseases, including cancer. Targeting mitochondria metabolism in tumors as a cancer therapeutic strategy has attracted much attention for researchers in recent years due to the essential role of mitochondria in cancer cell growth, apoptosis, and progression. On the other hand, a series of studies have indicated that traditional medicinal herbs, including traditional Chinese medicines (TCM), exert their potential anticancer effects as an effective adjunct treatment for alleviating the systemic side effects of conventional cancer therapies, for reducing the risk of recurrence and cancer mortality and for improving the quality of patients’ life. An amazing feature of these structurally diverse bioactive components is that majority of them target mitochondria to provoke cancer cell-specific death program. The aim of this review is to summarize the in vitro and in vivo studies about the role of these herbs, especially their bioactive compounds in the modulation of the disturbed mitochondrial function for cancer therapy.

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