title: Prohibitin 1 modulates mitochondrial function of Stat3.
abstract: Mitochondrial dysfunction in intestinal epithelial cells (IEC) is thought to precede the onset of inflammatory bowel diseases (IBD). Expression of Prohibitin 1 (PHB), a mitochondrial protein required for optimal electron transport chain (ETC) activity, is decreased in mucosal biopsies during active and inactive IBD. In addition to its activities as a transcription factor, Signal Transducer and Activator of Transcription 3 (Stat3) resides in the mitochondria of cells where phosphorylation at S727 is required for optimal ETC activity and protects against stress-induced mitochondrial dysfunction. Here, we show that PHB overexpression protects against mitochondrial stress and apoptosis of cultured IECs induced by TNFα, which is a pro-inflammatory cytokine involved in IBD pathogenesis. Expression of pS727-Stat3 dominant negative eliminates protection by PHB against TNFα-induced mitochondrial stress and apoptosis. PHB interacts with pS727-Stat3 in the mitochondria of cultured IECs and in colonic epithelium from wild-type mice. Our data suggest a protective role of PHB that is dependent on pS727-Stat3 to prevent mitochondrial dysfunction in IECs. Reduced levels of PHB during IBD may be an underlying factor promoting mitochondrial dysfunction of the intestinal epithelium.
authors: Department of Internal Medicine, Division of Gastroenterology, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, United States.
authors: Jie
authors: J
authors: Han
authors: Department of Medicine, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical Center, Dallas, TX, United States.
authors: Chunhua
authors: C
authors: Yu
authors: Department of Medicine, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical Center, Dallas, TX, United States.
authors: Rhonda F
authors: RF
authors: Souza
authors: Department of Internal Medicine, Division of Gastroenterology, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, United States. Electronic address: arianne.theiss@baylorhealth.edu.
authors: Arianne L
authors: AL
authors: Theiss
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018938:Caco-2 Cells; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D010766:Phosphorylation; D000091402:Prohibitins; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C000717328:PHB protein, human; D000091402:Prohibitins; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha
keywords: Electron transport chain; Intestinal epithelium; Mitochondria; Oxidative stress; Prohibitin; Stat3