| Summary: | Mitochondria are quantifiably the most important sources of superoxide (O<sub>2</sub><sup>●</sup><sup>−</sup>) and hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) 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 H<sub>2</sub>O<sub>2</sub>, also plays a vital role in the transmission of cellular information. Striking a balance between utilizing H<sub>2</sub>O<sub>2</sub> in second messaging whilst avoiding its deleterious effects requires the use of sophisticated feedback control and H<sub>2</sub>O<sub>2</sub> degrading mechanisms. Mitochondria are enriched with H<sub>2</sub>O<sub>2</sub> degrading enzymes to desensitize redox signals. These organelles also use a series of negative feedback loops, such as proton leaks or protein <i>S</i>-glutathionylation, to inhibit H<sub>2</sub>O<sub>2</sub> production. Understanding how mitochondria produce ROS is also important for comprehending how these organelles use H<sub>2</sub>O<sub>2</sub> 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 H<sub>2</sub>O<sub>2</sub> 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 H<sub>2</sub>O<sub>2</sub> 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.
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