The Mitochondrial Production of Reactive Oxygen Species: Mechanisms and Implications in Human Pathology

Abstract

SummaryMitochondria are major sources of reactive oxygen species (ROS); the main sites of superoxide radical production in the respiratory chain are Complexes III and I; however, other mitochondrial enzymes, such as Complex II, glycerol-1-phosphate dehydrogenase, and dihydroorotate dehydrogenase, are also involved in production of ROS. ROS appear to be released both in the matrix and in the intermembrane space; however, their appearance outside the mitochondria may not be physiologically relevant. ROS production is increased in State 4 and in all conditions when the respiratory components are substantially in the reduced form. Accordingly, defects inducing decrease of electron transfer in the respiratory chain, as in many pathological conditions, are bound to enhance ROS production.

Mitochondrial function, content and ROS production in rat skeletal muscle: Effect of high‐fat feeding

“…In the process of mitochondrial ATP synthesis, formation of reactive oxygen species (ROS) is an inevitable event that can be significantly enhanced by excessive fuel supply or functional impairment of one or more complexes of the respiratory chain [23]. If a high fat supply to the muscle induces mitochondrial dysfunction, one may anticipate that mitochondrial ROS production increases, further aggravating mitochondrial damage and dysfunction.…”

Uncoupling protein-2 deficiency promotes oxidant stress and delays liver regeneration in mice

“…8 -10 The process of oxidative phosphorylation inherently generates superoxide anion, which is formed by single electrons escaping their regular path along the respiratory chain and directly reducing molecular oxygen. 9,11 Superoxide production is enhanced if the rate of electron transport is limited by hyperpolarization of the inner mitochondrial membrane subsequent to the buildup of a large proton gradient that occurs with overwhelming fuel supply or with the functional impairment of one or more electron transport complexes. 9,10,12,13 Uncoupling protein-2 (UCP2), a recently identified inner mitochondrial membrane anion carrier, 14,15 has emerged as a sensor 16,17 and potentially critical negative regulator of mitochondrial superoxide production.…”

“…9,11 Superoxide production is enhanced if the rate of electron transport is limited by hyperpolarization of the inner mitochondrial membrane subsequent to the buildup of a large proton gradient that occurs with overwhelming fuel supply or with the functional impairment of one or more electron transport complexes. 9,10,12,13 Uncoupling protein-2 (UCP2), a recently identified inner mitochondrial membrane anion carrier, 14,15 has emerged as a sensor 16,17 and potentially critical negative regulator of mitochondrial superoxide production. 18,19 UCP2 is able to mediate proton leaks in mammalian cells 20 and keep the membrane potential sufficiently low to minimize superoxide production.…”

Alzheimer’s Disease: Focus on the Neuroprotective Role of Melatonin

“…Damage to the mitochondrial respiratory chain can cause breakdown of the mitochondrial membrane proton potential, opening of the mitochondrial permeability transition pore (mtPTP) and consequent induction of apoptosis, leading to further generation of free radicals and maintaining a vicious cycle that ultimately results in cell death by either necrotic or apoptotic processes [20]. Findings from a number of studies reveal the involvement of mitochondrial ROS production and subsequent mitochondrial abnormalities in the pathophysiology of AD [21].…”

“…In neuroblastoma cells, melatonin normalized trk and neurotrophin expression [50]. A schematic diagram showing melatonin's neuroprotective actions is presented in Table 1 AD not only depends upon its radical scavenging actions but also on its additional actions, including protecting the mitochondrial membranes and mitochondrial DNA from oxidative insults, stimulation of glutathione (GSH) synthesis, reduction of oxidized glutathione (GSSG) levels and maintenance of mitochondrial electron flux [20]. The electron transport chain (ETC) represents a major source of reactive oxygen species (ROS) within the cell [51].…”