Mitochondrial toxicity of organic arsenicals: membrane permeability transition pore opening and respiratory dysfunction

Abstract

In order to clarify the mitochondrial toxicity mechanism of the organic arsenical (2-methoxy-4-(((4-(oxoarsanyl) phenyl) imino) methyl) phenol), research was carried out at the sub-cell level based on the previous finding that the compound can damage the mitochondria by triggering a burst of ROS. After investigating its influence on isolated mitochondria , it was demonstrated that a high dose of with short-term exposure can induce mitochondrial swelling, decrease the membrane potential, enhance the permeability of H and K, and induce membrane lipid peroxidation, indicating that it can result in an MPT process in a ROS-mediated and Ca-independent manner. Additionally, MPT was also aggravated as a result of impairment of the membrane integrity and membrane fluidity. In addition, short-term incubation between mitochondria and compound promoted the inhibition of respiratory chain complexes I, II, III and IV, as well as damage to the respiration process, which supported the previous finding about the burst of ROS. On the other hand, after long-term exposure by the organic arsenical, mitochondrial metabolic dysfunction was triggered, which was in accordance with perturbation of the respiratory chain complexes as well as the respiration process. This work systematically sheds light on the mitochondrial toxicity mechanism of the organic arsenical , including induction of the MPT process and inhibition of respiratory metabolism, which provides a potential target for organic arsenicals as anti-tumor drugs.

Copper and cadmium administration induce toxicity and oxidative stress in the marine flatworm Macrostomum lignano

“…The O2•-and H2O2are not only dominating reactive oxygen species (ROS), but also facilitate other forms of ROS generation [11]. Fan et al [12] showed that mitochondria can be damaged by triggering a burst of ROS. Nevertheless, the reactive nature of ROS renders them potentially lethal [13].…”

Mitochondrial toxicity induced by a thiourea gold(i) complex: mitochondrial permeability transition and respiratory deficit

“…For the K + permeabilization test, solution K was introduced. 31 The detection method was similar to that of the swelling experiment.…”

Targeting of the respiratory chain by toxicants: beyond the toxicities to mitochondrial morphology

“…35 Fan et al reported that a short-term incubation of mitochondria in vitro with the organic arsenical MOPIMP promoted the inhibition of respiratory chain complexes I, II, III and IV, and with damage to the respiration process. 19 The activity of complex IV, the terminal complex of the electron transport chain, was significantly destroyed even when treated with MOPIMP at a low concentration level. Yu et al observed that AuTuCl altered the mitochondrial permeability transition as well as impairing the functioning of the mitochondrial respiratory chain.…”

“…Notably, compared to the well addressed and broadly reported studies of mitochondrial structure and morphology changes, the effects of environmental toxicants on the assembly and activity of mitochondrial RC supercomplexes, intact electron transport chain (ETC), and oxidative phosphorylation function remain incompletely understood and need to be intensively investigated. Recently, Fan et al 19 and Yu et al, 20 both from the State Key Laboratory of Virology, Wuhan University, China, approached this topic by closely examining the mitochondrial toxicities, including the effect on respiratory chain function, induced by organic arsenical chemical 2-methoxy-4-(((4-(oxoarsanyl)phenyl)imino)methyl)phenol (MOPIMP) 19 and thiourea gold(I) complexes (AuTuCl). 20 The generation of ATP in mitochondria requires a functional electron transport chain (ETC) and the oxidative phosphorylation system (OXPHOS).…”

“…We consider the articles by Fan et al 19 and Yu et al 20 as featured articles as they provided significant insights into the molecular function alterations of the RC by such toxicants, and have further enriched our knowledge on the molecular initiating events (MIE) and models of action (MOA) of environmental toxicants. Especially, the data from such studies are valuable in developing the Adverse Outcome Pathway (AOP) for mitochondrial toxicology.…”