Reactive Oxygen Species in Metabolic and Inflammatory Signaling

Abstract

Reactive oxygen species (ROS) are well known for their role in mediating both physiological and pathophysiological signal transduction. Enzymes and subcellular compartments that typically produce ROS are associated with metabolic regulation, and diseases associated with metabolic dysfunction may be influenced by changes in redox balance. In this review, we summarize the current literature surrounding ROS and their role in metabolic and inflammatory regulation, focusing on ROS signal transduction and its relationship to disease progression. In particular, we examine ROS production in compartments such as the cytoplasm, mitochondria, peroxisome, and endoplasmic reticulum and discuss how ROS influence metabolic processes such as proteasome function, autophagy, and general inflammatory signaling. We also summarize and highlight the role of ROS in the regulation metabolic/inflammatory diseases including atherosclerosis, diabetes mellitus, and stroke. In order to develop therapies that target oxidative signaling, it is vital to understand the balance ROS signaling plays in both physiology and pathophysiology, and how manipulation of this balance and the identity of the ROS may influence cellular and tissue homeostasis. An increased understanding of specific sources of ROS production and an appreciation for how ROS influence cellular metabolism may help guide us in the effort to treat cardiovascular diseases.

Keywords: cardiovascular diseases; inflammation; metabolism; oxidative stress; signal transduction.

Figure 1. Cytosolic ROS production and regulation of cytosolic metabolic pathways

Cytosolic ROS are formed most notably through NOX activity and influence metabolic processes including glycolysis and downstream oxidative phosphorylation, pentose phosphate pathway activity and autophagy. Please refer to the abbreviation table for full names of listed proteins.

Figure 2. Mitochondrial ROS production

MitoROS are produced as a normal byproduct of mitochondrial respiration and metabolic enzymatic activity. Under settings of increased ROS generation as a result of dysregulated enzymatic activity and cellular stress, mitoROS can influence metabolic pathways including the Krebs cycle, fatty acid synthesis, ATP generation, glycolysis and mitophagy. Cyto=cytoplasm, IMS=intermembrane space, LPP=lipid peroxidation product. Please refer to the abbreviation table for full names of listed proteins.

Figure 3. Peroxisomal ROS and metabolism

PeroxROS are produced as byproducts of enzymatic reactions within β-oxidation, polyamine synthesis, D-amino acid deamination and hypoxanthine oxidation, and have been found to be key regulators of pexophagy. Full names of abbreviations are listed in the accompanying table.

Figure 4. Endoplasmic reticulum and ROS

The ER is highly sensitive to redox status, and altered ROS signaling can influence protein folding, Ca²⁺ release and mitochondrial respiration. Please refer to the abbreviation table for full names of depicted proteins.

Figure 5. Inflammation and ROS

Various inflammation-inducing stimuli including TNFα, LPS, thrombin and oscillatory shear stress influence ROS production through sources including NOX and the mitochondria. Elevated ROS production as a result of inflammatory signaling can mediate canonical NF-κB activation and downstream inflammatory gene induction, proteasome activity, antioxidant gene transcription, inflammasome activation and cytokine secretion. Full names for abbreviations are listed in the accompanying table.