A radical shift in perspective: mitochondria as regulators of reactive oxygen species

Abstract

Mitochondria are widely recognized as a source of reactive oxygen species (ROS) in animal cells, where it is assumed that overproduction of ROS leads to an overwhelmed antioxidant system and oxidative stress. In this Commentary, we describe a more nuanced model of mitochondrial ROS metabolism, where integration of ROS production with consumption by the mitochondrial antioxidant pathways may lead to the regulation of ROS levels. Superoxide and hydrogen peroxide (H 2 O 2 ) are the main ROS formed by mitochondria. However, superoxide, a free radical, is converted to the non-radical, membrane-permeant H 2 O 2 ; consequently, ROS may readily cross cellular compartments. By combining measurements of production and consumption of H 2 O 2 , it can be shown that isolated mitochondria can intrinsically approach a steady-state concentration of H 2 O 2 in the medium. The central hypothesis here is that mitochondria regulate the concentration of H 2 O 2 to a value set by the balance between production and consumption. In this context, the consumers of ROS are not simply a passive safeguard against oxidative stress; instead, they control the established steady-state concentration of H 2 O 2 . By considering the response of rat skeletal muscle mitochondria to high levels of ADP, we demonstrate that H 2 O 2 production by mitochondria is far more sensitive to changes in mitochondrial energetics than is H 2 O 2 consumption; this concept is further extended to evaluate how the muscle mitochondrial H 2 O 2 balance should respond to changes in aerobic work load. We conclude by considering how differences in the ROS consumption pathways may lead to important distinctions amongst tissues, along with briefly examining implications for differing levels of activity, temperature change and metabolic depression.

Cell size control – a mechanism for maintaining fitness and function

“…Interestingly, the relationship between hepatic DNA content and lipid metabolism is comparable to non-alcoholic fatty liver disease patients who display a significant increase in polyploid hepatocytes [68]. Moreover, it has been observed that the increase in polyploidy in hepatocytes during NAFLD progression is due to excess of lipids causing increased oxidative stress [68], which is indicative of mitochondrial malfunction [69].…”

“…This implicates that in hepatocytes with increase in cell size and polyploidy, mitochondrial activity is reduced and ATP production likely compensated by enhanced glycolytic activity, resulting in substantial metabolic remodelling. Moreover, it has been observed that the increase in polyploidy in hepatocytes during NAFLD progression is due to excess of lipids causing increased oxidative stress [68], which is indicative of mitochondrial malfunction [69]. Moreover, it has been observed that the increase in polyploidy in hepatocytes during NAFLD progression is due to excess of lipids causing increased oxidative stress [68], which is indicative of mitochondrial malfunction [69].…”

Sex differences in cancer mechanisms

“…Today, numerous studies have shown that cancer cells also exploit the mitochondrial tricarboxylic acid cycle (TCA cycle) and oxidative phosphorylation [190,191]. Mitochondria are a primary source of reactive oxygen species (ROS), and ROS production and consumption through mitochondrial antioxidant pathways, such as glutathione oxidation, are required for well-balanced regulation of ROS levels [192]. Mitochondria exhibit a strong sex-specific behavior as they are exclusively maternally inherited.…”

NADPH‐oxidase‐derived ROS alters cell migration by modulating adhesions dynamics

“…We can observe three mainly forms of ROS at cell: superoxide (O − 2 ), hydrogen peroxide (H 2 O 2 ) and hydroxyl free radicals ( * OH) [Chen et al, 2008]. In animal cells, these species are produced mainly by the electron transport chain at mitochondria, but also produced by enzymatic sources, such as dual oxidases, nitric oxide synthases and NADPH oxidase complex [Munro and Treberg, 2017;Ushio-Fukai, 2006]. These compounds have high reactivity suggesting that ROS can be used to regulate specific signalling pathways at specific cells regions, for…”