An Update on Mitochondrial Reactive Oxygen Species Production

Abstract

Mitochondria are quantifiably the most important sources of superoxide (O2●−) and hydrogen peroxide (H2O2) in mammalian cells. The overproduction of these molecules has been studied mostly in the contexts of the pathogenesis of human diseases and aging. However, controlled bursts in mitochondrial ROS production, most notably H2O2, also plays a vital role in the transmission of cellular information. Striking a balance between utilizing H2O2 in second messaging whilst avoiding its deleterious effects requires the use of sophisticated feedback control and H2O2 degrading mechanisms. Mitochondria are enriched with H2O2 degrading enzymes to desensitize redox signals. These organelles also use a series of negative feedback loops, such as proton leaks or protein S-glutathionylation, to inhibit H2O2 production. Understanding how mitochondria produce ROS is also important for comprehending how these organelles use H2O2 in eustress signaling. Indeed, twelve different enzymes associated with nutrient metabolism and oxidative phosphorylation (OXPHOS) can serve as important ROS sources. This includes several flavoproteins and respiratory complexes I-III. Progress in understanding how mitochondria generate H2O2 for signaling must also account for critical physiological factors that strongly influence ROS production, such as sex differences and genetic variances in genes encoding antioxidants and proteins involved in mitochondrial bioenergetics. In the present review, I provide an updated view on how mitochondria budget cellular H2O2 production. These discussions will focus on the potential addition of two acyl-CoA dehydrogenases to the list of ROS generators and the impact of important phenotypic and physiological factors such as tissue type, mouse strain, and sex on production by these individual sites.

Mitochondrial Glutathione: Recent Insights and Role in Disease

“…Within the cells, mitochondria are not only the primary site of oxygen consumption, but also the major source of reactive oxygen species (ROS), most of them originating at the electron transport chain (ETC). For a recent review on the subject, see [ 18 ]. During mitochondrial respiration some “leakiness”, or partial reduction reactions occur, mainly from complexes I and III even under physiologic conditions ( Figure 2 ).…”

The Universal Soldier: Enzymatic and Non-Enzymatic Antioxidant Functions of Serum Albumin

“…Mitochondria are a powerful source of cellular ROS and contain a number of enzymes that convert molecular oxygen to superoxide or its derivative hydrogen peroxide [ 7 , 8 ]. Because of the leak of electrons from the mitochondrial enzyme complexes I and III, about 2–5% of molecular oxygen is converted into the active form.…”

“…Moreover, monoamine oxidase and cytochrome-β5 reductase in the outer mitochondrial membrane, glycerol-3-phosphate dehydrogenase and cytochrome P450 in inner mitochondrial membrane, and matrix enzymes aconitase, pyruvate dehydrogenase and α-ketoglutarate dehydrogenase can produce the superoxide radical [ 3 ]. Currently, long-chain fatty acid dehydrogenase (LCAD) and very long-chain fatty acid dehydrogenase (VLCAD) are discussed as candidates to be added to the list of mitochondrial ROS generators [ 8 ].…”

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“…ψm is also a crucial indicator for mitochondrial health and, if dissipated, may signal the cell to perform various stress responses or even mitochondrial mediated apoptosis (Mitchell, 2011). However, ROS are generated from up to 12 different enzymes associated with nutrient metabolism and OXPHOS, including several flavoproteins and respiratory complexes I-III (Gorrini et al, 2013;Mailloux, 2020). ROS are highly reactive and can imbalance cellular reduction-oxidization (redox) and readily oxidize proteins, lipids, carbohydrates, DNA, and RNA causing oxidative damage if in excess.…”

“…ROS are highly reactive and can imbalance cellular reduction-oxidization (redox) and readily oxidize proteins, lipids, carbohydrates, DNA, and RNA causing oxidative damage if in excess. To protect organelles from ROS oxidative damage, mitochondria develop their own antioxidative system, such as the protective antioxidative manganese superoxide dismutase 2 (SOD2) enzymes and the glutathione/glutathione peroxidase/glutathione reductase axis (Beer et al, 2004;Lin et al, 2018;Mailloux, 2020) With its close association with the OXPHOS system, the mitochondrial genome is subject to ROS assault (Saki and Prakash, 2017). Thus, mitochondria are heavily dependent on antioxidative enzymes encoded by the nuclear genome (Kazak et al, 2012).…”