Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients

Abstract

Fukushima, Kouhei, and Claudio Fiocchi. Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients. Am J Physiol Gastrointest Liver Physiol 286: G804-G813, 2004; 10.1152/ajpgi.00398.2003.-Ulcerative colitis (UC) is a condition characterized by chronic inflammation targeted at the epithelial layer. In addition to being involved in immune phenomena, UC epithelial cells exhibit decreased oxidation of butyrate, downregulation of oxidative pathway regulatory genes, and overexpression of mitochondrial (mt) genes. We investigated whether these events, which translate an altered energy metabolism, are associated with an abnormal pattern of mtDNA deletions. Highly purified colonocytes were isolated from surgically resected control, involved and uninvolved inflammatory bowel disease mucosa. The frequency, type, and number of mtDNA deletions were assessed by PCR amplification, Southern blot analysis, and cloning and sequencing of amplified DNA fragments. The 4977 mtDNA deletion was less frequent in UC than control and Crohn's disease (CD) epithelium, regardless of patient age. Several other deletions were detected, but all were less common in UC than control and CD cells. The frequency, variety, and number of mtDNA deletions were invariably lower in colonocytes isolated from inflamed mucosa than in autologous cells from noninflamed mucosa. In conclusion, in the absence of inflammation, UC colonocytes exhibit an mtDNA deletion pattern similar to that of control cells, indicating a normal response to physiological levels of oxidative stress. In active inflammation, when oxidative stress increases, the frequency, variety, and number of mtDNA deletions decrease. Because comparable abnormalities are absent in active CD, the mtDNA deletion pattern of active UC suggests that colonocytes respond uniquely to inflammation-associated stress in this condition. epithelium; energy metabolism ALTHOUGH THE ETIOLOGY OF ULCERATIVE colitis (UC) is still uncertain, colonic epithelial cells (EC) have long been considered central to its pathophysiology. In addition to the restriction of the inflammatory process and associated dysplastic changes to the epithelial lining (43), there is abundant experimental evidence pointing to colonocytes as likely targets and mediators of key pathogenic events. Detection of circulating colon antibodies and cytotoxic mononuclear cells in UC patients initially suggested that colonocytes could be targets of autoimmune reactivity (6, 49). Subsequent studies demonstrated that in UC, EC express high levels of human leukocyte antigen D-related antigens (48), secrete abnormal mucin glycoconjugates (41), produce increased amounts of cytokines and chemokines (4,42,57), express costimulatory molecules (39), display autoantigens recognized exclusively by UC tissueeluted antibodies (53), and fail to mediate induction of suppressor T cells (36). Additional reports demonstrated cyclooxygenase 2 and NF-B activation (46, 51), as well as an increased rate of EC apoptosis in UC (...

The 4977bp deletion of mitochondrial DNA in human skeletal muscle, heart and different areas of the brain: A useful biomarker or more?

“…In case of human oocytes it has been confirmed that age exhibits the only significant correlation with the presence of the 4977 bp deletion, while other parameters like smoking or early follicular phase FSH did not reveal any correlation (Chan et al, 2005). In recent years, a number of carefully conducted studies reported, that the level of the 4977 bp deletion is not increased in different tumour tissues (Dani et al, 2004;Dai et al, 2006;Ye et al, 2007) and in conditions associated with chronic inflammation like ulcerative colitis (Fukushima and Fiocchi, 2004). Though our data display a great variability even in individuals of the same age group, the large pool of data may help to discriminate between physiological ageing and pathological conditions associated with accelerated ageing.…”

Nutriproteomics: technologies and applications for identification and quantification of biomarkers and ingredients

“…Rho GDI alpha (Rho GDP-dissociation inhibitor 1), L-lactate dehydrogenase A, etc.). In ulcerative colitis patients, forty differentially expressed proteins were identified among which thirteen were associated with energy metabolism, which is in line with chronic intestinal inflammation being characterised by energy deficiency and alteration of the oxidative metabolism of epithelial cells (185,186) .…”

Mitochondria at the Interface Between Danger Signaling and Metabolism: Role of Unfolded Protein Responses in Chronic Inflammation

“…During the last years, accumulating evidence implicated ER UPR at the epithelial cell level in promotion and perpetuation of intestinal inflammation,24, 128, 129 and at the same time, it has been repeatedly suggested that chronic intestinal inflammation represents an energy‐deficiency disease involving mitochondria and featuring alterations in epithelial cell oxidative metabolism 25, 130. Inflammation and ER stress are linked at many levels, since inflammation is characterized by the production of large amounts of proteins such as cytokines or chemokines and, furthermore, ER UPR signaling can directly intersect with inflammatory pathways including NF‐κB, JNK, TLR‐mediated signaling and production of ROS 131–134.…”

“…Various metabolically driven and inflammatory diseases feature activated ER UPR1–3, 7 and both ER‐ and mtUPR are associated with IBD24 14. Also, mitochondrial dysfunction and alterations in energy metabolism in general have been implicated during the onset and course of neoplasia, metabolic diseases, and inflammation 21, 23, 25. Beyond their well‐established functions in cell metabolism and during apoptosis, mitochondria have gained increasing attention for their role in innate immune signaling 26–29.…”