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.
Highlights
The overproduction of ROS by dysfunctional mitochondria and its association with pathogenesis and ageing has been a topic of study for many years
It has recently been demonstrated that several organisms have extended lifespans when mitochondrial ROS production is high for short periods of time [3]
Just like long-chain fatty acid dehydrogenase (LCAD), the individual native rate of ROS production by very long-chain fatty acid dehydrogenase (VLCAD) should be compared to the other known mitochondrial ROS generators to ascertain its contribution to overall O2 − /H2 O2 emission during fatty acid oxidation (FAO). Based on this preliminary evidence, it may be that the list of potential mitochondrial ROS generators may be expanded to fourteen, with LCAD and VLCAD being added to the UQH2 /UQ isopotential group
Summary
The overproduction of ROS by dysfunctional mitochondria and its association with pathogenesis and ageing has been a topic of study for many years. Like any other second messenger, H2 O2 signals need to be desensitized following a response to a physiological cue This is achieved with antioxidant defenses, negative feedback loops that inhibit production, assembly and disassembly of supercomplexes, and proton leaks, which allows cells to use mitochondrial H2 O2 for signaling whilst avoiding its deleterious effects (reviewed extensively in [10]). Our group recently demonstrated that other key physiological and phenotypic factors must be considered when studying how mitochondria maintain cellular ROS balance This includes factors such as mouse strain and sex and tissue type, which can have a strong impact on the native rate of H2 O2 production by several “unconventional” ROS generators such as α-keto acid dehydrogenases [12].
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