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Characterization of cyanide-insensitive respiration in mitochondria and submitochondrial particles of Moniliella tomentosa.

ABSTRACT: Mitochondria and submitochondrial particles of the osmophilic yeast-like fungus Moniliella tomentosa may respire by means of two pathways: a normal cytochrome pathway, sensitive to cyanide and antimycin A, and an alternative pathway, which is insensitive to these inhibitors but is specifically inhibited by salicylhydroxamic acid. The affinities of both oxidases for succinate and NADH as substrates, for O(2) as terminal electron acceptor, and for AMP as stimulator of the alternative oxidase were determined. 1. Submitochondrial particles of M. tomentosa may also respire by means of a cyanide-sensitive and/or cyanide-insensitive system. 2. The activities of both oxidases as compared with the total activity are roughly the same in submitochondrial particles as in the original mitochondria. 3. The terminal oxidase of the cyanide-insensitive pathway requires a 10-fold higher O(2) concentration for saturation than does cytochrome c oxidase. 4. The apparent K(m) for succinate is about 3 times higher for the alternative than for the normal oxidase when measured in mitochondria, and 4-10 times higher when measured in submitochondrial particles. The apparent K(m) for NADH is roughly the same for both oxidases. 5. The apparent K(m) values of both oxidases for succinate are always lower in submitochondrial particles than in mitochondria. 6. The apparent K(m) for AMP, acting as a stimulator of the alternative oxidase, is the same (25mum) in mitochondria as in sub-mitochondrial particles. These results are discussed in the light of the structure and localization of the components of the alternative oxidase.

SUBMITTER: Vanderleyden J

PROVIDER: S-EPMC1161325 | biostudies-other | 1979 Aug

REPOSITORIES: biostudies-other

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Project description:Single-walled carbon nanotubes can induce mitochondrial F0F1-ATPase nanotoxicity through inhibition. To completely characterize the mechanistic effect triggering the toxicity, we have developed a new approach based on the combination of experimental and computational study, since the use of only one or few techniques may not fully describe the phenomena. To this end, the in vitro inhibition responses in submitochondrial particles (SMP) was combined with docking, elastic network models, fractal surface analysis, and Nano-QSTR models. In vitro studies suggest that inhibition responses in SMP of F0F1-ATPase enzyme were strongly dependent on the concentration assay (from 3 to 5 µg/mL) for both pristine and COOH single-walled carbon nanotubes types (SWCNT). Besides, both SWCNTs show an interaction inhibition pattern mimicking the oligomycin A (the specific mitochondria F0F1-ATPase inhibitor blocking the c-ring F0 subunit). Performed docking studies denote the best crystallography binding pose obtained for the docking complexes based on the free energy of binding (FEB) fit well with the in vitro evidence from the thermodynamics point of view, following an affinity order such as: FEB (oligomycin A/F0-ATPase complex) = -9.8 kcal/mol > FEB (SWCNT-COOH/F0-ATPase complex) = -6.8 kcal/mol ~ FEB (SWCNT-pristine complex) = -5.9 kcal/mol, with predominance of van der Waals hydrophobic nano-interactions with key F0-ATPase binding site residues (Phe 55 and Phe 64). Elastic network models and fractal surface analysis were performed to study conformational perturbations induced by SWCNT. Our results suggest that interaction may be triggering abnormal allosteric responses and signals propagation in the inter-residue network, which could affect the substrate recognition ligand geometrical specificity of the F0F1-ATPase enzyme in order (SWCNT-pristine > SWCNT-COOH). In addition, Nano-QSTR models have been developed to predict toxicity induced by both SWCNTs, using results of in vitro and docking studies. Results show that this method may be used for the fast prediction of the nanotoxicity induced by SWCNT, avoiding time- and money-consuming techniques. Overall, the obtained results may open new avenues toward to the better understanding and prediction of new nanotoxicity mechanisms, rational drug design-based nanotechnology, and potential biomedical application in precision nanomedicine.

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Characterization of cyanide-insensitive respiration in mitochondria and submitochondrial particles of Moniliella tomentosa.

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