Mechanism of Mitochondrial Uncouplers, Inhibitors, and Toxins: Focus on Electron Transfer, Free Radicals, and Structure -Activity Relationships

Abstract

The biology of the mitochondrial electron transport chain is summarized. Our approach to the mechanism of uncouplers, inhibitors, and toxins is based on electron transfer (ET) and reactive oxygen species (ROS). Extensive supporting evidence, which is broadly applicable, is cited. ROS can be generated either endogenously or exogenously. Generally, the reactive entities arise via redox cycling by ET functionalities, such as, quinones (or precursors), metal compounds, imines (or iminiums), and aromatic nitro compounds (or reduced metabolites). In most cases, the ET functions are formed metabolically. The toxic substances belong to many categories, e.g., medicinals, industrial chemicals, abused drugs, and pesticides. Structure-activity relationships are presented from the ET-ROS perspective, and also quantitatively. Evidence for the theoretical framework is provided by the protective effect of antioxidants. Among other topics addressed are proton flux, membrane pores, and apoptosis. There is support for the thesis that mitochondrial insult may contribute to illnesses and aging.

Antioxidants in Wild Mushrooms

“…Superoxide anion can also be produced by different endogenous enzymatic systems present in the cell like NADPH oxidases and xanthine oxidase [3,19]. O 2 • have been implicated in several diseases [21].…”

Antioxidant properties of benzoic acid derivatives against Superoxide radical

“…During energy transduction, a small number of electrons leaks to oxygen prematurely, forming the oxygen free radical superoxide, which has been implicated in pathophysiology of variety diseases. [3] In healthy subjects, it has been estimated that approximately 1.7-17 kg per year of dioxygen is converted to O 2.-and hence this is likely the most abundant oxygen radical in the human body. [4] This radical is believed to be responsible for O 2 toxicity in living organisms.…”

Antioxidant peptides isolated from sea cucumber Stichopus Japonicus

“…The consequences evocated by ROS are very serious, extensive evidences implicate the pathophysiology of a variety of diseases [5]. It was suggested that free radical damage to cells leads to the pathological changes associated with aging [6], and free radicals may be a contributory factor in a progressive decline in the function of the immune system [7].…”