Reactive Oxygen Species as a Link between Antioxidant Pathways and Autophagy

Abstract

Reactive oxygen species (ROS) are highly reactive molecules that can oxidize proteins, lipids, and DNA. Under physiological conditions, ROS are mainly generated in the mitochondria during aerobic metabolism. Under pathological conditions, excessive ROS disrupt cellular homeostasis. High levels of ROS result in severe oxidative damage to the cellular machinery. However, a low/mild level of ROS could serve as a signal to trigger cell survival mechanisms. To prevent and cope with oxidative damage to biomolecules, cells have developed various antioxidant and detoxifying mechanisms. Meanwhile, ROS can initiate autophagy, a process of self-clearance, which helps to reduce oxidative damage by engulfing and degrading oxidized substance. This review summarizes the interactions among ROS, autophagy, and antioxidant pathways. The effects of natural phytochemicals on autophagy induction, antioxidation, and dual-function are also discussed.

Figure 1

Schematic representation of redox-sensitive transcription factor-related antioxidant pathways. (a) Nrf2 pathway: when cells are exposed to ROS, Nrf2 dissociates from Keap1 and transfers into the nucleus, binding to ARE and regulating transcriptions of various antioxidant and lysosomal and autophagic genes [42]. Nrf2 activators, i.e., sulforaphane, show their protective effect against oxidative stress based on the Nrf2 signaling cascade [72]. (b) FoxO pathway: once activated by ROS, FoxO (mainly FoxO1 and FoxO3) transfers to the nucleus to initiate transcriptional activity [48]. Under oxidative stress, FoxO1 forms a complex with SIRT1 and deacetylates, resulting in preferential activation of autophagic and lysosomal genes [124]. Meanwhile, AKT, regulated by SIRT1, can phosphorylate FoxO3 proteins, thereby promoting the transcriptional activity of antioxidant-related genes. Resveratrol, gossypol acetic acid, etc., as FoxO activators, are reported to prevent chronic diseases by preventing oxidative stress and upregulate level of autophagy [125, 126].

Figure 2

ROS regulates TFEB-dependent autophagy promotion. Lysosomes are activated by mitochondrial ROS, followed by lysosomal Ca²⁺ release and calcineurin activation. Calcineurin bound to Ca²⁺ dephosphorylates TFEB. Then, nuclear-localized TFEB causes the transcription of a series of genes, including autophagy induction, autophagosome biogenesis, lysosomal biogenesis, and autolysosome biogenesis [60, 69]. Autophagy is enhanced to promote the removal of damaged mitochondria and excess ROS [127]. Among them, a low level of oxidative stress will stimulate lysosomal exocytosis, but at a high level, it will inhibit lysosomal exocytosis [128].

Figure 3

Dual-activating (antioxidant and autophagy) pathways. Dual-target activators such as sulforaphane induce a low level of ROS to activate the Nrf2-dependent antioxidant pathway and TFEB-dependent lysosomal biogenesis and autophagy, thereby helping to remove excess ROS [72]. A working model to illustrate the role of Nrf2/TFEB in sulforaphane-mediated enhancement of autophagic and lysosomal function. Sulforaphane (for example, through mitochondria and other sources) stimulates low level of ROS, which activates the Nrf2 pathway and the release of Ca²⁺. Ca²⁺-bound calcineurin dephosphorylates TFEB, causing TFEB nuclear translocation [129]. Nuclear Nrf2/TFEB then promotes the transcription of a unique set of genes related to detoxifying enzymes, autophagy induction, and autophagic and lysosomal biogenesis [130]. Subsequently, the cells are promoted to remove damaged mitochondria and excess ROS (the figure is adapted from Li et al. [72]).