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.

Keywords: ROS; complex I; mitochondria; redox signaling; reverse electron transport.

Figure 1

Respiratory CI produces ROS in both the forward and reverse direction. (A) During forward electron transfer (FET), CoQ receives electrons from complexes I and II, DHODH, G3P and ETFQO. During this process electrons mainly leak to produce superoxide from the I_F site of CI during the oxidation of NADH to NAD+. (B) In these conditions, if rotenone blocks the I_Q site, electrons cannot be transferred to CoQ, leak and generate ROS. FCCP also increases mtROS generation during FET. (C) When the CoQ pool becomes over-reduced, a high membrane potential favors the reverse transfer of electrons from ubiquinol to CI in a process called reverse electron transport (RET). During RET electrons leak at either I_F or I_Q generating a significant amount of superoxide. (D) Blocking the I_Q site with rotenone during RET prevents CoQ from transferring electrons back to CI and reduces ROS production. Similarly, FCCP reduces ROS by dissipating membrane potential.

Figure 2

Reverse electron transfer (RET) as a new ROS-based mitochondrial signaling pathway. The redox state of the CoQ pool determines electron leak and superoxide production and can be used by mitochondria as a signaling mechanism. Since RET is sensitive to changes in electron flow and membrane potential, it can be used to detect changes in energy supply and fine-tune cell metabolism. For example, an increase in the availability fatty acid alters the NADH:FADH2 ratio from 5:1 to 2:1 and in response levels of CI are reshuffled by ROS produced via RET (RET-ROS) (Guaras et al., 2016).