Role of Mitochondrial Reverse Electron Transport in ROS Signaling: Potential Roles in Health and Disease

Abstract

Reactive Oxygen Species (ROS) can cause oxidative damage and have been proposed to be the main cause of aging and age-related diseases including cancer, diabetes and Parkinson's disease. Accordingly, mitochondria from old individuals have higher levels of ROS. However, ROS also participate in cellular signaling, are instrumental for several physiological processes and boosting ROS levels in model organisms extends lifespan. The current consensus is that low levels of ROS are beneficial, facilitating adaptation to stress via signaling, whereas high levels of ROS are deleterious because they trigger oxidative stress. Based on this model the amount of ROS should determine the physiological effect. However, recent data suggests that the site at which ROS are generated is also instrumental in determining effects on cellular homeostasis. The best example of site-specific ROS signaling is reverse electron transport (RET). RET is produced when electrons from ubiquinol are transferred back to respiratory complex I, reducing NAD+ to NADH. This process generates a significant amount of ROS. RET has been shown to be instrumental for the activation of macrophages in response to bacterial infection, re-organization of the electron transport chain in response to changes in energy supply and adaptation of the carotid body to changes in oxygen levels. In Drosophila melanogaster, stimulating RET extends lifespan. Here, we review what is known about RET, as an example of site-specific ROS signaling, and its implications for the field of redox biology.

The role of mitochondrial ROS in the aging brain

“…This could result in the presence of mitochondria that are not ‘suited’ to perform the specific tasks required in a particular cell or location. These ‘misplaced’ mitochondria could generate more ROS in order to activate their own turnover since the mitochondria have mechanisms to sense dysfunction (e.g., RET ). Chronically high levels of ROS could potentially trigger oxidative stress and contribute to the saturation of quality control mechanisms, which would spread the damage .…”

Tricarboxylic acid cycle metabolites in the control of macrophage activation and effector phenotypes

“…Concomitant with the oxidation of succinate, SDH transfers reducing equivalents into the quinone pool, which normally follows forward electron transport to Complex III and IV. However, in M LPS macrophages, these reducing equivalents follow reverse electron transport (RET) and are transferred to Complex I, which was found to be responsible for mitochondrial ROS‐dependent HIF‐1α stabilization and IL‐1β production . This is particularly interesting because M LPS macrophages also produce NO, which impairs forward electron flow .…”

The global regulator Crc orchestrates the metabolic robustness underlying oxidative stress resistance in Pseudomonas aeruginosa

“…Considering that about 90% of the ROS formed in bacteria under oxic growth conditions are generated by the electronic transport chain (ETC) (Scialò et al, 2017;Maklashina et al, 2018), the specific rates of respiration and O 2 Á − formation were assessed in the strains under study ( Fig. 4).…”