Abstract:These results suggest that UC has a dual mitochondrial and nuclear genetic control that warrants further replication in independent data sets and reinforces its etiopathogenic complexity.
“… 60 Importantly, mitochondrial-encoded DNA polymorphisms have been identified to be associated with UC in European cohorts. 61 , 62 Furthermore, 5% of genes highlighted by IBD genome-wide association studies were functionally linked to the maintenance of mitochondrial health, further underpinning the role of deregulated mitochondrial function in IBD. 63 Figure 1.…”
Section: Mitochondria–microbiota Cross Talk and Implication In Intestmentioning
The gastrointestinal microbiome plays a pivotal role in physiological homeostasis of the intestine as well as in the pathophysiology of diseases including inflammatory bowel diseases (IBD) and colorectal cancer (CRC). Emerging evidence suggests that gut microbiota signal to the mitochondria of mucosal cells, including epithelial cells and immune cells. Gut microbiota signaling to mitochondria has been shown to alter mitochondrial metabolism, activate immune cells, induce inflammasome signaling, and alter epithelial barrier function. Both dysbiosis of the gut microbiota and mitochondrial dysfunction are associated with chronic intestinal inflammation and CRC. This review discusses mitochondrial metabolism of gut mucosal cells, mitochondrial dysfunction, and known gut microbiota-mediated mitochondrial alterations during IBD and CRC.
“… 60 Importantly, mitochondrial-encoded DNA polymorphisms have been identified to be associated with UC in European cohorts. 61 , 62 Furthermore, 5% of genes highlighted by IBD genome-wide association studies were functionally linked to the maintenance of mitochondrial health, further underpinning the role of deregulated mitochondrial function in IBD. 63 Figure 1.…”
Section: Mitochondria–microbiota Cross Talk and Implication In Intestmentioning
The gastrointestinal microbiome plays a pivotal role in physiological homeostasis of the intestine as well as in the pathophysiology of diseases including inflammatory bowel diseases (IBD) and colorectal cancer (CRC). Emerging evidence suggests that gut microbiota signal to the mitochondria of mucosal cells, including epithelial cells and immune cells. Gut microbiota signaling to mitochondria has been shown to alter mitochondrial metabolism, activate immune cells, induce inflammasome signaling, and alter epithelial barrier function. Both dysbiosis of the gut microbiota and mitochondrial dysfunction are associated with chronic intestinal inflammation and CRC. This review discusses mitochondrial metabolism of gut mucosal cells, mitochondrial dysfunction, and known gut microbiota-mediated mitochondrial alterations during IBD and CRC.
“…The etiology of inflammatory bowel diseases is multifocal. That is, it involves several factors, such as the environment, microbiota, epithelial barrier dysfunction, perturbed immune systems, cellular oxidative stress, and genetic alterations (10)(11)(12)(13)(14)(15). Among them, thus far, the genetic changes in nuDNA (16,17) have been the main focus, only a few studies about mtDNA having been conducted (18).…”
“…Moreover, dysfunction of MT-ND4 has been described in the context of experimental autoimmune encephalomyelitis, which is an animal model of multiple sclerosis [ 33 ], breast cancer [ 34 ], cystic fibrosis [ 35 ] and other diseases. Most interestingly, a recent report in a small cohort of UC patients could bring a different mitochondrial DNA variant affecting MT-ND4 into relation to UC, which underlines the possible relevance for intestinal homeostasis [ 18 ]. Of note, we found the association only for male subjects.…”
Section: Discussionmentioning
confidence: 99%
“…We recently described that variants in mitochondrial DNA determine mucosal ATP levels and susceptibility to experimental colitis in mice [ 17 ]. In addition, in a small European UC cohort a mitochondrial polymorphism was just recently described to be associated with UC [ 18 ]. However, mitochondrial SNPs are usually excluded from genetic associations studies, so we aimed at investigating the role of mitochondrial gene variations in the development of UC.…”
BackgroundUlcerative colitis (UC) is a chronic inflammatory disorder of still unknown pathogenesis. Increasing evidence indicates that alterations in mitochondrial respiration and thus adenosine triphosphate (ATP) production are involved. This may contribute to mucosal energy deficiency and subsequently intestinal barrier malfunction, which is accepted to be a major hallmark of UC. Genetic alterations of the mitochondrial genome are one cause of mitochondrial dysfunction. However, less is known about mitochondrial gene polymorphisms in UC. Therefore, we aimed at identifying genetic associations between mitochondrial polymorphisms and UC.MethodsGerman UC cases (n = 1062) and German healthy controls (n = 3030) were genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0. The primary association analysis was to test for associations between mitochondrial single nucleotide polymorphisms (SNPs) and UC using Fisher’s exact test in the total sample and stratified by sex. In addition, we tested for associations between mitochondrial haplogroups and UC and for interactions between the most promising mitochondrial SNPs and nuclear SNPs. An independent set of German subjects with 1625 UC cases and 3575 controls was used for replication.ResultsWe identified a genetic association between the MT-ND4 11719 A/G polymorphism and UC in the subgroup of males (rs2853495; odds ratio, 1.40; 95 % confidence interval, 1.13 to 1.73; p = 0.002). This association was replicated in the second independent cohort. In the association analysis based on mitochondrial haplogroups the lowest p values were reached for haplogroups HV and T (p = 0.029 and 0.035). Haplogroup HV is determined by the mitochondrial 11719 A/G polymorphism. Accordingly, this association was only found in the subgroup of males (p = 0.009).ConclusionsFor the first time, we observed an association between the MT-ND4 11719 A/G polymorphism and UC. The gene MT-ND4 encodes for a subunit of the mitochondrial electron transport chain complex I, which is pivotal for ATP production and might therefore contribute to mucosal energy deficiency. The male-specific association indicates differences between males and females concerning the impact of mitochondrial gene polymorphisms on the development of UC. Further investigations of the functional mechanism underlying this association and the relevance of the gender-specificity are highly warranted.Electronic supplementary materialThe online version of this article (doi:10.1186/s12876-016-0509-1) contains supplementary material, which is available to authorized users.
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