Translocator Protein-Mediated Stabilization of Mitochondrial Architecture during Inflammation Stress in Colonic Cells.

Abstract

UNLABELLED:

Chronic inflammation of the gastrointestinal tract increasing the risk of cancer has been described to be linked to the high expression of the mitochondrial translocator protein (18 kDa; TSPO). Accordingly, TSPO drug ligands have been shown to regulate cytokine production and to improve tissue reconstruction. We used HT-29 human colon carcinoma cells to evaluate the role of TSPO and its drug ligands in tumor necrosis factor (TNF)-induced inflammation. TNF-induced interleukin (IL)-8 expression, coupled to reactive oxygen species (ROS) production, was followed by TSPO overexpression. TNF also destabilized mitochondrial ultrastructure, inducing cell death by apoptosis. Treatment with the TSPO drug ligand PK 11195 maintained the mitochondrial ultrastructure, reducing IL-8 and ROS production and cell death. TSPO silencing and overexpression studies demonstrated that the presence of TSPO is essential to control IL-8 and ROS production, so as to maintain mitochondrial ultrastructure and to prevent cell death. Taken together, our data indicate that inflammation results in the disruption of mitochondrial complexes containing TSPO, leading to cell death and epithelia disruption.

SIGNIFICANCE:

This work implicates TSPO in the maintenance of mitochondrial membrane integrity and in the control of mitochondrial ROS production, ultimately favoring tissue regeneration.

• Authors: Leeyah Issop, Mariano A Ostuni, Sunghoon Lee, Mireille Laforge, Gabriel Péranzi, Pierre Rustin, Jean-François Benoist, Jérome Estaquier, Vassilios Papadopoulos, Jean-Jacques Lacapère
• Journal: PloS one (PLoS One) Vol. 11 Issue 4 Pg. e0152919 ( 2016) ISSN: 1932-6203 [Electronic] United States
• PMID: 27054921 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CXCL8 protein, human
• Interleukin-8
• Neoplasm Proteins
• Reactive Oxygen Species
• Receptors, GABA
• TSPO protein, human
• Tumor Necrosis Factor-alpha

Topics

• Cell Death
• Cell Line, Tumor
• Colon (metabolism, pathology)
• Colonic Neoplasms (metabolism, pathology)
• Gene Expression Regulation, Neoplastic
• Humans
• Inflammation (chemically induced, metabolism, pathology)
• Interleukin-8 (biosynthesis)
• Mitochondria (metabolism, pathology)
• Mitochondrial Membranes (metabolism, pathology)
• Neoplasm Proteins (biosynthesis)
• Reactive Oxygen Species (metabolism)
• Receptors, GABA (biosynthesis)
• Stress, Physiological
• Tumor Necrosis Factor-alpha (adverse effects, pharmacology)