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

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.

LiveMalasseziastrains isolated from the mucosa of patients with ulcerative colitis

“…A DSS-induced colitis mouse model was developed using 6-week-old female C57BL/6 mice (Koatech, Pyeongtaek, Korea), as described previously 89 . Colitis was induced using 2.5% DSS (molecular weight: 36,000-50,000 kDa, MP Biomedicals, Santa Ana, CA, USA) for five days, followed by water for two days (i.e., a total of seven days).…”

Role of Mitochondria in Inflammatory Bowel Diseases: A Systematic Review

“…Interestingly, treatment with the antioxidant N-acetylcysteine ameliorated the signs of colitis, apoptosis and oxidative stress, highlighting the important role of ROS in the pathophysiology of IBD. A study of Rubicon further discusses the role of mitochondrial ROS in IBD [25]. Rubicon is a positive regulator of the NADPH oxidase complex and it is involved in autophagy and inflammatory responses.…”

Colon-Targeted eNAMPT-Specific Peptide Systems for Treatment of DSS-Induced Acute and Chronic Colitis in Mouse

“…As previously described, DSS-induced acute or chronic colitis mouse models were developed using 6-week-old C57BL/6 female mice (Samtako, Osan, Republic of Korea) [ 36 ]. To assess the trigger of acute colitis, mice were treated with 3% ( w / v ) dextran sodium sulfate (molecular weight: 36,000–50,000 kDa, MP Biomedicals, Santa Ana, CA, USA) dissolved in drinking water that was given ad libitum.…”

“…Four-millimeter paraffin slices were cut and stained with hematoxylin and eosin (H&E). As previously mentioned, a board-certified pathologist (Dr. Min-Kyung Kim, Kim Min-Kyung Pathology Clinic, Seoul, Korea) independently scored each organ segment without prior knowledge of the therapy groups [ 36 ].…”