Mito-TIPTP Increases Mitochondrial Function by Repressing the Rubicon-p22phox Interaction in Colitis-Induced Mice.

Jae-Sung Kim,Hyo-Keun Kim,Euni Cho,Seok-Jun Mun,Hye-In Jeon,Ye-Ram Kim,Chul-Su Yang,Sun-Joon Min,Sein Jang,Sang Geon Wang

doi:10.3390/antiox10121954

Jae-Sung Kim, Hyo-Keun Kim + Show 8 more

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https://doi.org/10.3390/antiox10121954

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Abstract

The run/cysteine-rich-domain-containing Beclin1-interacting autophagy protein (Rubicon) is essential for the regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase by interacting with p22phox to trigger the production of reactive oxygen species (ROS) in immune cells. In a previous study, we demonstrated that the interaction of Rubicon with p22phox increases cellular ROS levels. The correlation between Rubicon and mitochondrial ROS (mtROS) is poorly understood. Here, we report that Rubicon interacts with p22phox in the outer mitochondrial membrane in macrophages and patients with human ulcerative colitis. Upon lipopolysaccharide (LPS) activation, the binding of Rubicon to p22phox was elevated, and increased not only cellular ROS levels but also mtROS, with an impairment of mitochondrial complex III and mitochondrial biogenesis in macrophages. Furthermore, increased Rubicon decreases mitochondrial metabolic flux in macrophages. Mito-TIPTP, which is a p22phox inhibitor containing a mitochondrial translocation signal, enhances mitochondrial function by inhibiting the association between Rubicon and p22phox in LPS-primed bone-marrow-derived macrophages (BMDMs) treated with adenosine triphosphate (ATP) or dextran sulfate sodium (DSS). Remarkably, Mito-TIPTP exhibited a therapeutic effect by decreasing mtROS in DSS-induced acute or chronic colitis mouse models. Thus, our findings suggest that Mito-TIPTP is a potential therapeutic agent for colitis by inhibiting the interaction between Rubicon and p22phox to recover mitochondrial function.

Highlights

Oxygen-derived free radicals, such as superoxide and hydroxide, are known as reactive oxygen species (ROS) and are small, highly reactive molecules
As colitis is associated with activation of the NLRP3 inflammasome, we used adenosine triphosphate (ATP)- or dextran sulfate sodium (DSS)-activated macrophages to examine the interaction between Rubicon and p22phox in vitro
Rubicon interacted with p22phox primarily in the mitochondria of colon lysates from ulcerative colitis subjects, but not healthy controls (Figure 8B). These results indicate that of Rubicon and p22phox in the colon are clinically significant in ulcerative colitis, suggesting that they may serve as biomarkers for ulcerative colitis

Summary

Introduction

Oxygen-derived free radicals, such as superoxide and hydroxide, are known as reactive oxygen species (ROS) and are small, highly reactive molecules. ROS plays an important role in both physiological and pathological cellular responses, depending on ROS concentration. ROS production is tightly regulated to specific subcellular sites and involves complex cellular signaling and negative feedback mechanisms. Under specific conditions, excessive ROS production results in oxidative stress, causing damage to host intracellular systems, and various diseases, such as sepsis, inflammatory bowel diseases (IBDs), atherosclerosis, heart failure, cancer, aging, and neurodegeneration [1,2,3]. Mitochondria are membrane-bound organelles that are essential for maintaining energy through oxidative phosphorylation and other metabolic functions

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