MitoTarget Modeling Using ANN-Classification Models Based on Fractal SEM Nano-Descriptors: Carbon Nanotubes as Mitochondrial F0F1-ATPase Inhibitors

Abstract

Recently, it has been suggested that the mitochondrial oligomycin A-sensitive F0-ATPase subunit is an uncoupling channel linked to apoptotic cell death, and as such, the toxicological inhibition of mitochondrial F0-ATP hydrolase can be an interesting mitotoxicity-based therapy under pathological conditions. In addition, carbon nanotubes (CNTs) have been shown to offer higher selectivity like mitotoxic-targeting nanoparticles. In this work, linear and nonlinear classification algorithms on structure−toxicity relationships with artificial neural network (ANN) models were set up using the fractal dimensions calculated from CNTs as a source of supramolecular chemical information. The potential ability of CNT-family members to induce mitochondrial toxicity-based inhibition of the mitochondrial H + -F0F1-ATPase from in vitro assays was predicted. The attained experimental data suggest that CNTs have a strong ability to inhibit the F0-ATPase active-binding site following the order oxidized−CNT (CNT−COOH > CNT−OH) > pristine−CNT and mimicking the oligomycin A mitotoxicity behavior. Meanwhile, the performance of the ANN models was found to be improved by including different nonlinear combinations of the calculated fractal scanning electron microscopy (SEM) nanodescriptors, leading to models with excellent internal accuracy and predictivity on external data to classify correctly CNT-mitotoxic and nonmitotoxic with specificity (Sp > 98.9%) and sensitivity (Sn > 99.0%) from ANN models compared with linear approaches (LNN) with Sp ≈ Sn > 95.5%. Finally, the present study can contribute toward the rational design of carbon nanomaterials and opens new opportunities toward mitochondrial nanotoxicology-based in silico models.

New Mechanistic Insights on Carbon Nanotubes’ Nanotoxicity Using Isolated Submitochondrial Particles, Molecular Docking, and Nano-QSTR Approaches

“…The relevance of these results is that strong local perturbations similar to those observed in Figure 4A, B are able to induce strong allosteric perturbations in the j-effector residues from the F0-ATPase receptor, affecting its mitochondrial catalytic function (ATP-hydrolysis) involving the signal transduction of the perturbations from the block of i-sensor residues which trigger abnormal signals' propagation across the inter-residue network for j-effector F0-ATPase residues. We could suggest that considering the SWCNT docking position, both ligands (SWCNT-pristine >> SWCNT-COOH) can theoretically disrupt the H + -proton flux dynamic in the mitochondrial H + -F0-ATPase subunit, compromising the coupling between oxidative phosphorylation and electron transport in the respiratory chain, inducing potential bioenergetic dysfunction and the mitochondria nanotoxicity [9]. In order to quantify potential fractal geometrical perturbations, a fractal surface analysis was carried out to model changes-based perturbations in the geometric surface of the binding effector residues of the F0-ATPase under unbound and bound states (i.e., under SWCNT-pristine and SWCNT-COOH interactions) [9].…”

“…As a consequence, the ATP cellular reserves are abruptly consumed by a reverse biochemical reaction which paradoxically hydrolyses significant amounts of ATP, compromising the cellular homeostasis and viability [3,5,6]. Several chemical agents (including carbon nanoparticles) have shown a high affinity/selectivity by the bioenergetic mechanisms based on ATP hydrolysis, particularly nanoparticle-based single-walled carbon nanotubes (SWCNTs), which have been studied by their selective nanotoxicity effects on mitochondria (mitotropic behavior) [7][8][9][10].…”

“…To the best of our knowledge, the toxicological modulation of mitochondrial ATP bioenergetic mechanisms released by the exposure with SWCNT-pristine and oxidized-SWCNT (SWCNT-COOH) have been insufficiently characterized in order to explain the mitochondrial nanotoxicity induced by SWCNT. On the other hand, this mechanistic knowledge could be very useful to implement strategies on the named "precision mitochondrial nanomedicine" to improve selectivity for the treatment of brain, cardiac diseases, and cancer using the mitotropic behavior of SWCNT to address active pharmacological principles as new targeting of the mitochondrial F0F1-ATPase [9][10][11][12][13][14]. In this context, we hypothesize that SWCNT-pristine could act by mimicking the pharmacodynamic behavior of the Oligomycin A, which is the specific inhibitor of the mitochondrial ATP-hydrolysis that modulates the activity of the c-ring-F0-ATP hydrolase subunit.…”

“…In this regard, computational approaches like molecular docking simulation, elastic network models, fractal surface approaches linked to nano-quantitative structureactivity/toxicity relationships (Nano-QSAR/QSTR models), and others [9,[20][21][22][23], could be efficiently applied to the exhaustive exploration of the underlying mechanisms of mitochondrial bioenergetic dysfunction (pathological ATP-hydrolysis) from the structural point of view for therapeutic purposes.…”

“…Another relevant approach to study toxicity is computational nano-quantitative structure-activity/toxicity relationships (nano-QSAR/QSTR), which are essential tools to support the discovery process of toxicological effects of nanomaterials (SWCNT). Several approaches have been developed and applied recently to predict potential harmfulness of nanoparticles and nanomaterials [9][10][11][12][13][14]29]. These in silico tools have the quality of being versatile and reconfigurable to many problems.…”