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 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.

Effects of 6-hydroxydopamine on oxidative phosphorylation of mitochondria from rat striatum, cortex, and liver

1988 ◽  
Vol 66 (3) ◽  
pp. 376-379 ◽  
Author(s):  
J. H. Thakar ◽  
M. N. Hassan
Keyword(s):  
Oxidative Phosphorylation ◽  
Incubation Medium ◽  
Respiratory Control ◽  
Rat Striatum ◽  
Respiratory Control Ratio ◽  
Chemical Sympathectomy ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Consumption Ratio ◽  
6 Hydroxydopamine

The catecholamine neurotoxin 6-hydroxydopamine (6-OHDA) has been used to produce cardiac chemical sympathectomy as well as a model of parkinsonism. Several mechanisms have been proposed to explain its cytotoxicity, including the productions of quinones, hydrogen peroxide, and free radicals by autooxidation and the uncoupling of mitochondrial oxidative phosphorylation. We have observed that 6-OHDA at a concentration of 0.05 mM rapidly consumes oxygen from the mitochondrial incubation medium but does not affect oxidative phosphorylation in the mitochondria from rat striatum, cortex, and liver. At the higher concentration of 0.5 mM, 6-OHDA consumes all of the available oxygen from the incubation medium. Mitochondria exposed to this concentration of 6-OHDA show decreases in the respiratory control ratio and adenosine triphosphate synthesis as measured by the consumption ratio of ADP to oxygen. Thus, only the higher (0.5 mM) concentration of 6-OHDA, which produces anoxia in vitro, also causes mitochondrial damage.

scholarly journals Influence of ubiquinone on the inhibitory effect of adriamycin on mitochondrial oxidative phosphorylation

1984 ◽  
Vol 217 (2) ◽  
pp. 493-498 ◽  
Author(s):  
H Muhammed ◽  
C K R Kurup
Keyword(s):  
Oxidative Phosphorylation ◽  
Rat Heart ◽  
Liver Mitochondria ◽  
Inhibitory Effect ◽  
Oxidative Activity ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Succinate Oxidation ◽  
Exogenous Addition

The inhibition of succinate oxidation in both heart and liver mitochondria by the cardiotoxic anticancer antibiotic adriamycin in vitro was reversed to a large extent by exogenous ubiquinone-45. Inhibition of the oxidation of NAD+-linked substrates in heart and liver mitochondria responded differently to ubiquinone, the inhibition being reversed only in liver organelles. Administration of adriamycin inhibited oxidative phosphorylation in rat heart, kidney and liver mitochondria, the inhibition being highest in the heart organelles (about 50% for both NAD+-linked substrates and succinate). Exogenous addition of ubiquinone to mitochondria isolated from drug-treated animals did not reverse the inhibition. Administration of ubiquinone along with adriamycin did not change effectively the pattern of drug-mediated decrease in oxidative activity of the organelles, particularly in the heart.

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 Respiratory Mitochondrial Efficiency and DNA Oxidation in Human Sperm after In Vitro Myo-Inositol Treatment

2020 ◽  
Vol 9 (6) ◽  
pp. 1638 ◽  
Author(s):  
Laura Governini ◽  
Rosetta Ponchia ◽  
Paolo Giovanni Artini ◽  
Elena Casarosa ◽  
Ilaria Marzi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Oxidative Phosphorylation ◽  
Oxidative Damage ◽  
Sperm Motility ◽  
Semen Quality ◽  
Sperm Quality ◽  
Antioxidant Properties ◽  
Atp Production ◽  
In Vitro Treatment

Semen samples are known to contain abnormal amounts of reactive oxygen species (ROS) and oxygen free radicals; therefore, the identification of antioxidant molecules able to counteract the oxidative damage caused by ROS is foresight. Indeed, improving semen quality in terms of motility and reduction in DNA damage, can significantly improve the fertilization potential of sperm in vitro. To this regard, myo-inositol, based on its antioxidant properties, has been reported to be effective in improving sperm quality and motility in oligoasthenozoospermic patients undergoing assisted reproduction techniques when used as a dietary supplementation. Moreover, in vitro treatment demonstrated a direct relationship between myo-inositol, mitochondrial membrane potential and sperm motility. This experimental study aimed to evaluate the effects of myo-inositol (Andrositol-lab) in vitro treatment on sperm motility, capacitation, mitochondrial oxidative phosphorylation and DNA damage. Our results demonstrate that myo-inositol induces a significant increase in sperm motility and in oxygen consumption, the main index of oxidative phosphorylation efficiency and ATP production, both in basal and in in vitro capacitated samples. Moreover, we provide evidence for a significant protective role of myo-inositol against oxidative damage to DNA, thus supporting the in vitro use of myo-inositol in assisted reproductive techniques. Even if further studies are needed to clarify the mechanisms underlying the antioxidant properties of myo-inositol, the present findings significantly extend our knowledge on human male fertility and pave the way to the definition of evidence-based guidelines, aiming to improve the in vitro procedure currently used in ART laboratory for sperm selection.

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.

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)

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