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Manganese porphyrins are well-known protectors against the deleterious effects of pro-oxidant species such as superoxide ions and hydrogen peroxide. The present study investigated the antioxidant cytochrome c-like activities of Mn(III)TMPyP [meso-tetrakis (4-N-methyl pyridinium) porphyrin] against superoxide ion and hydrogen peroxide that remained unexplored for this porphyrin. The association of TMPyP with a model of the inner mitochondrial membrane, cardiolipin (CL)-containing liposomes, shifted +30 mV vs. NHE (normal hydrogen electrode) redox potential of the Mn (II) /Mn (III) redox couple. In CL-containing liposomes, Mn (III) TMPyP was reduced by superoxide ions and recycled by Fe (III) cytochrome c to the oxidized form. Similarly, isolated rat liver mitoplasts added to a sample of Mn (II) TMPyP promoted immediate porphyrin reoxidation by electron transfer to the respiratory chain. These results show that Mn (III) TMPyP can act as an additional pool of Fe (III) cytochrome c capable of transferring electrons that escape from the IV complex back into the respiratory chain. Unlike Fe (II) cytochrome c, Mn (II) TMPyP was not efficient for hydrogen peroxide clearance. Therefore, by reducing cytochrome c, Mn (II) TMPyP can indirectly contribute to hydrogen peroxide elimination., Competing Interests: Declaration of competing interest Authors declare no conflicts of interest and no competing interests., (Copyright © 2021 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

The effect of four trichlorotelluro-dypnones, named compounds 1, 2, 3, and 4, on the bioenergetics of isolated rat liver mitochondria (RLM) and cells was investigated. In a dose-dependent manner, the studied organotelluranes promoted Ca(2+)-dependent mitochondrial swelling inhibited by cyclosporine A and were associated with a decrease of the total mitochondrial protein thiol content. These effects characterize the opening of the classical mitochondrial permeability transition pore. Despite the reactivity with mitochondrial protein thiol groups, these compounds did not promote significant glutathione depletion. In the absence of Ca(2+), the organotelluranes promoted mitochondrial loss of ΔΨ in RLM concomitant with respiratory control decrease due to an increase of the state 4 respiration rate. In these conditions, mitochondrial swelling was absent, and thiol content was higher than that in the presence of Ca(2+). The differentiated effects observed in the presence and absence of Ca(2+) are probably related to the effects of that ion on membrane structure, with repercussions for the exposure of specific reactive protein thiol groups. In smooth muscle cells, these compounds promoted the loss of mitochondrial ΔΨ and apoptosis. The loss of ΔΨ was not preceded by a decrease of cell viability that is consistent with mitochondria as the primary targets for the action of these organotelluranes.

Aerobic organisms are afforded with an antioxidant enzymatic apparatus that more recently has been recognized to include cytochrome c, as it is able to prevent hydrogen peroxide generation by returning electrons from the superoxide ion back to the respiratory chain. The present study investigated the glutathione peroxidase (GPx), superoxide dismutase (SOD) and cytochrome c-like antioxidant activities of para Mn(III)TMPyP in isolated rat liver mitochondria (RLM) and mitoplasts. In RLM, Mn(III)TMPyP decreased the lipid-peroxide content associated with glutathione (GSH) depletion consistent with the use of GSH as a reducing agent for high valence states of Mn(III)TMPyP. SOD and cytochrome c antioxidant activities were also investigated. Mn(II)TMPyP was able to reduce ferric cytochrome c, indicating the potential to remove a superoxide ion by returning electrons back to the respiratory chain. In antimicyn A-poisoned mitoplasts, Mn(III)TMPyP efficiently decreased the EPR signal of DMPO-OH adduct concomitant with GSH depletion. The present results are consistent with SOD and GPx activities for Mn(III)TMPyP and do not exclude cytochrome c-like activity. However, considering that para Mn(III)TMPyP more efficiently reduces, rather than oxidizes, superoxide ion; electron transfer from the Mn(II)TMPyP to the respiratory chain might not significantly contribute to the superoxide ion removal, since most of Mn(II)TMPyP is expected to be produced at the expense of NADPH/GSH oxidation. The present results suggest GPx-like activity to be the principal antioxidant mechanism of Mn(III)TMPyP, whose efficiency is dependent on the NADPH/GSH content in cells.