Mitochondrial Production of Oxygen Radical Species and the Role of Coenzyme Q as an Antioxidant

Abstract

The mitochondrial respiratory chain is a powerful source of reactive oxygen species (ROS), which is considered as the pathogenic agent of many diseases and of aging. We have investigated the role of complex I in superoxide radical production and found by the combined use of specific inhibitors of complex I that the one-electron donor to oxygen in the complex is a redox center located prior to the sites where three different types of Coenzyme Q (CoQ) competitors bind, to be identified with an Fe-S cluster, most probably N2, or possibly an ubisemiquinone intermediate insensitive to all the above inhibitors. Short-chain Coenzyme Q analogs enhance superoxide formation, presumably by mediating electron transfer from N2 to oxygen. The clinically used CoQ analog, idebenone, is particularly effective, raising doubts on its safety as a drug. Cells counteract oxidative stress by antioxidants. CoQ is the only lipophilic antioxidant to be biosynthesized. Exogenous CoQ, however, protects cells from oxidative stress by conversion into its reduced antioxidant form by cellular reductases. The plasma membrane oxidoreductase and DT-diaphorase are two such systems, likewise, they are overexpressed under oxidative stress conditions.

mt-Nd2 Allele of the ALR/Lt mouse confers resistance against both chemically induced and autoimmune diabetes

“…Mitochondria (mt) play key roles in cellular energy production and cell death, as well as representing the major source of intracellularly generated oxygen free radicals during normal metabolism [1]. Peroxidation by reactive oxygen species (ROS) of mt cardiolipin leads to dissociation of cytochrome c from the mt inner membrane, a step required for initiating apoptotic cell death [2].…”

Reductive Stress Linked to Small HSPs, G6PD, and Nrf2 Pathways in Heart Disease

“…This is particularly essential within the mammalian heart, which could not produce enough energy to maintain essential cellular functions under anaerobic conditions (45). However, a small percentage (1%-2%) of the molecular oxygen consumed is incompletely reduced during this process (43,86), resulting in the generation of highly reactive, partially reduced products of oxygen within the cell. These oxygen-derived pro-oxidants, or reactive oxygen species (ROS) are highly damaging to the cell if allowed to accumulate in large amounts, a process that increases with aging ( Fig.…”

Mitochondria and Antioxidants: The Active Players in Islet Oxidative Stress

“…In other words, if an inhibitor blocks the very entry of Complex I at the site of FMN and prevents the access of electrons into Complex I at all, it would prevent ROS generation. If an inhibitor blocks electron flow somewhere in the middle of Complex I and allows redox centers upstream of the block to be over-reduced, it would result in an increase of ROS (Genova et al 2003). In accordance with this notion, inhibitory effects of diphenylene iodonium on ROS induced by hyperglycemia in MIN-6 cells were reported by (Tsubouchi et al 2005), though the researchers attributed this fact solely to the plasma membrane NAD(P)H oxidase inhibition.…”