Circadian Control of Mitochondria in Reactive Oxygen Species Homeostasis

Mitochondria produce most of the cellular ATP through the process of oxidative phosphorylation. Energy metabolism in the mitochondria is associated with the production of reactive oxygen species (ROS). Excessive ROS production leads to oxidative stress and compromises cellular physiology. Energy metabolism in the mitochondria depends on nutrient flux and cellular metabolic needs, which are in turn connected with the feeding/fasting cycle. In animals, the feeding/fasting cycle is controlled by the circadian clock that generates 24-h rhythms in behavior, metabolism, and signaling. Here, we discuss the role of the circadian clock and rhythms in mitochondria on ROS homeostasis. The circadian clock is involved in mitochondrial ROS production and detoxification through the control of nutrient flux and oxidation, uncoupling, antioxidant defense, and mitochondrial dynamics. Little is known on the molecular mechanisms of circadian control of mitochondrial functions. The circadian clock regulates the expression and activity of mitochondrial metabolic and antioxidant enzymes. The regulation involves a direct transcriptional control by Circadian Locomotor Output Cycles Kaput/brain and muscle ARNT-like 1(CLOCK/BMAL1), nuclear factor erythroid-2-related factor 2 (NRF2) transcriptional network, and sirtuin-dependent posttranslational protein modifications. We hypothesize that the circadian clock orchestrates mitochondrial physiology to synchronize it with the feeding/fasting cycle. Circadian coordination of mitochondrial function couples energy metabolism with diets and contributes to antioxidant defense to prevent metabolic diseases and delay aging. Antioxid. Redox Signal. 37, 647-663.