The role of the mitochondrial protein VDAC1 in inflammatory bowel disease: a potential therapeutic target.

Abstract

Recent studies have implicated mitochondrial dysfunction as a trigger of inflammatory bowel diseases, including Crohn's disease (CD) and ulcerative colitis (UC). We have investigated the role of the mitochondria gate-keeper protein, the voltage-dependent-anion channel 1 (VDAC1), in gastrointestinal inflammation and tested the effects of the newly developed VDAC1-interacting molecules, VBIT-4 and VBIT-12, on UC induced by dextran sulfate sodium (DSS) or trinitrobenzene sulphonic acid (TNBS) in mice. VDAC1, which controls metabolism, lipids transport, apoptosis, and inflammasome activation, is overexpressed in the colon of CD and UC patients and DSS-treated mice. VBIT-12 treatment of cultured colon cells inhibited the DSS-induced VDAC1 overexpression, oligomerization, and apoptosis. In the DSS-treated mice, VBIT-12 suppressed weight loss, diarrhea, rectal bleeding, pro-inflammatory cytokine production, crypt and epithelial cell damage, and focal inflammation. VBIT-12 also inhibited the infiltration of inflammatory cells, apoptosis, mtDNA release, and activation of caspase-1 and NRLP3 inflammasome to reduce the inflammatory response. The levels of the ATP-gated P2X7-Ca2+/K+ channel and ER-IP3R-Ca2+ channel, and of the mitochondrial anti-viral protein (MAVS), mediating NLRP3 inflammasome assembly and activation, were highly increased in DSS-treated mice, but not when VBIT-12 treated. We conclude that UC may be promoted by VDAC1-overexpression and may therefore be amenable to treatment with novel VDAC1-interacting molecules. This VDAC1-based strategy exploits a completely new target for UC treatment and opens a new avenue for treating other inflammatory/autoimmune diseases.

• Authors: Ankit Verma, Srinivas Pittala, Belal Alhozeel, Anna Shteinfer-Kuzmine, Ehud Ohana, Rajeev Gupta, Jay H Chung, Varda Shoshan-Barmatz
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 30 Issue 2 Pg. 726-744 (02 02 2022) ISSN: 1525-0024 [Electronic] United States
• PMID: 34217890 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• Inflammasomes
• Mitochondrial Proteins
• VDAC1 protein, human
• Dextran Sulfate
• Voltage-Dependent Anion Channel 1

Topics

• Animals
• Colitis (chemically induced, drug therapy)
• Dextran Sulfate (adverse effects)
• Humans
• Inflammasomes (metabolism)
• Inflammatory Bowel Diseases (drug therapy)
• Mice
• Mitochondria (metabolism)
• Mitochondrial Proteins (metabolism)
• Voltage-Dependent Anion Channel 1 (genetics)