antimycin and Body-Weight

Defects in the mitochondrial respiratory chain (RC) underlie a spectrum of human conditions, ranging from devastating inborn errors of metabolism to aging. We performed a genome-wide Cas9-mediated screen to identify factors that are protective during RC inhibition. Our results highlight the hypoxia response, an endogenous program evolved to adapt to limited oxygen availability. Genetic or small-molecule activation of the hypoxia response is protective against mitochondrial toxicity in cultured cells and zebrafish models. Chronic hypoxia leads to a marked improvement in survival, body weight, body temperature, behavior, neuropathology, and disease biomarkers in a genetic mouse model of Leigh syndrome, the most common pediatric manifestation of mitochondrial disease. Further preclinical studies are required to assess whether hypoxic exposure can be developed into a safe and effective treatment for human diseases associated with mitochondrial dysfunction.

Topics: Anaerobiosis; Animals; Antimycin A; Bacterial Proteins; Biomarkers; Body Temperature; Body Weight; CRISPR-Associated Protein 9; Disease Models, Animal; Electron Transport; Electron Transport Complex I; Endonucleases; Energy Metabolism; Gene Knockout Techniques; Genome-Wide Association Study; Glycine; Humans; Hypoxia-Inducible Factor 1; Isoquinolines; K562 Cells; Leigh Disease; Mice; Mice, Knockout; Mitochondria; Oxygen; Respiration; Suppression, Genetic; Von Hippel-Lindau Tumor Suppressor Protein; Zebrafish

Here we investigate the possible involvement of the sympathetic nervous system in the respiratory properties of intermyofibrillar and subsarcolemmal mitochondrial populations from heart and gastrocnemius muscles. Mitochondrial oxidative phosphorylation was assessed polarographically by using succinate (plus rotenone), and ascorbate plus N,N,N',N'-tetramethyl-p-phenyl-enediamine (plus antimycin) as respiratory substrates. We report that chronic chemical sympathectomy with guanethidine (150 mg/kg, daily for 3 weeks) induced a marked decrease in whole body metabolic and heart rates, in plasma metabolites (fatty acids and glucose) and norepinephrine levels. Guanethidine treatment decreased mainly the oxidative phosphorylation capacity of subsarcolemmal mitochondria in heart, irrespective of the substrate used. In contrast, both mitochondrial populations were affected by the treatment in skeletal muscle. This suggests that sympathetic nervous system activity can alter the energetic status of muscle cells, and to some extent play a thermogenic role in birds.

Topics: Animals; Antimycin A; Ascorbic Acid; Body Weight; Catecholamines; Ducks; Fatty Acids; Glucose; Guanethidine; Heart Rate; Male; Mitochondria; Oxidative Phosphorylation; Oxygen; Rotenone; Sarcolemma; Succinic Acid; Tetramethylphenylenediamine; Uncoupling Agents

In this study the effect of dietary trans fatty acids on the peroxisomal and mitochondrial beta-oxidation is compared with that of saturated or cis-monounsaturated fatty acids. Oxidation of [1-14C]- and [16-14C]palmitate was assayed in the absence as well as in the presence of antimycin plus rotenone in homogenates of liver, heart and skeletal muscle of four groups of rats fed diets containing 40 energy% fat of different fatty acid composition. Three groups were given fat blends rich in C16, C18 saturated (cocoa butter), cis-monounsaturated (low-linoleic-acid olive oil) or trans fatty acids (partially hydrogenated soybean oil), respectively. The fourth group received a mixture of these fats with half the amount of trans fatty acids of the third group. Total oxidation rates of [1-14C]- and [16-14C]palmitate in the absence of antimycin were not significantly influenced by the type of dietary fat in the investigated tissues. The antimycin-insensitive [1-14C]palmitate oxidation rate and the proportion of peroxisomal oxidation of the total oxidation were lower in all tissues of those animals fed the mixed dietary fat than in those fed the other diets; both parameters were higher in the liver of cocoa butter-fed rats than in those of the other groups. Comparison of the results with literature data and with previous results obtained with a low-fat diet (Veerkamp and Van Moerkerk (1986) Biochim. Biophys. Acta 875, 301-310) indicates that high-fat diets only induce peroxisomal beta-oxidation activity if they also contain C20, C22 fatty acids. High dietary concentrations of trans C18 fatty acids do not result in a higher peroxisomal activity than that observed for other fatty acids with the same chain length.

Topics: Animals; Antimycin A; Body Weight; Dietary Fats; Fatty Acids; Fatty Acids, Unsaturated; Liver; Male; Microbodies; Mitochondria, Liver; Mitochondria, Muscle; Muscles; Myocardium; Oxidation-Reduction; Rats