A radical shift in perspective: mitochondria as regulators of reactive oxygen species.
Mitochondria are widely recognized as a source of reactive oxygen species (ROS) in animal cells, where it is assumed that over-production 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 (H2O2) are the main ROS formed by mitochondria. However, superoxide, a free radical, is converted to the non-radical, membrane-permeant H2O2; consequently, ROS may readily cross cellular compartments. By combining measurements of production and consumption of H2O2, it can be shown that isolated mitochondria can intrinsically approach a steady-state concentration of H2O2 in the medium. The central hypothesis here is that mitochondria regulate the concentration of H2O2 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 H2O2 By considering the response of rat skeletal muscle mitochondria to high levels of ADP, we demonstrate that H2O2 production by mitochondria is far more sensitive to changes in mitochondrial energetics than is H2O2 consumption; this concept is further extended to evaluate how the muscle mitochondrial H2O2 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.
['Munro|Daniel|D|', 'Treberg|Jason R|JR|0000-0001-5112-7325']
D000818:Animals D004734:Energy Metabolism D006801:Humans D006861:Hydrogen Peroxide D008928:Mitochondria D018482:Muscle, Skeletal D018384:Oxidative Stress D010101:Oxygen Consumption D017382:Reactive Oxygen Species D064348:Torpor
Antioxidant Oxidative stress Hydrogen peroxide Skeletal muscle Energetics Glutathione peroxidase Peroxiredoxin Thioredoxin