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• W2004709337 abstract "See “Mitochondrial gene polymorphisms that protect mice from colitis,” by Bär F, Bochmann W, Widok A, et al, on page 1055. See “Mitochondrial gene polymorphisms that protect mice from colitis,” by Bär F, Bochmann W, Widok A, et al, on page 1055. Within each eukaryotic cell there are 2 genomes, one encoded by nuclear DNA and the other by mitochondrial DNA (mtDNA). Unlike nuclear DNA, mtDNA can be present in hundreds of copies per cell. mtDNA is replicated and transcribed independently of nuclear DNA to produce (in humans and mice) 22 tRNAs and 2 rRNA genes that function to translate an additional 13 protein coding genes (Table 1). These mtDNA genes encode components for 4 of the 5 respiratory chain complexes of the mitochondrial inner membrane that function in oxidative phosphorylation and thus the production of cellular ATP. Oxidative phosphorylation, and to a lesser extent glycolysis, are the major sources of energy in cells, with mitochondrial respiration producing large quantities of ATP from each molecule of glucose. Sperm are packed with mitochondria at the base of the flagella to provide sufficient ATP to travel around 200,000 times their own length to the ovum, the equivalent of a 6-foot tall human swimming 350 km without stopping. These sperm-derived mitochondria do not typically become part of the embryo and therefore mtDNA is maternally derived in a non-Mendelian fashion. Mutations in mtDNA cause maternally inherited diseases owing to defective oxidative phosphorylation that include Leber hereditary optic neuropathy, Leigh syndrome, encephalopathies, such as MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) and myopathies, including MERRF (myoclonic epilepsy with ragged red fibers) syndrome and Kearns–Sayre syndrome. Mutations in mtDNA may also contribute susceptibility to complex genetic disorders including macular degeneration, Alzheimer disease, type 2 diabetes, and the metabolic syndrome.1Ruiz-Pesini E. Lott M.T. Procaccio V. et al.An enhanced MITOMAP with a global mtDNA mutational phylogeny.Nucleic Acids Res. 2007; 35: D823-D828Crossref PubMed Scopus (468) Google Scholar In this issue, Bar et al2Bär F. Bochmann W. Widok A. et al.Mitochondrial gene polymorphisms that protect mice from colitis.Gastroenterology. 2013; 145: 1055-1063Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar find that genetic polymorphisms in mtDNA protect mice from chemically induced colitis, suggesting that inflammatory bowel diseases (IBDs) might be added to the growing list of diseases that involve mtDNA mutations.Table 1mtDNA-encoded Genes and Examples of Human Diseases Caused by Their MutationMitochondrial GeneEncoded ProteinFunctionHuman Disease (Examples)MT-RNR1None (12S RNA)mtDNA translationNonsyndromic deafnessMT-RNR2Humanin? (16S RNA)Prosurvival factor?tRNAs (22 of these)NonemtDNA translationMELAS; MERRF syndrome; deafnessMT-ND1NADH dehydrogenase subunit 1ETC Complex ILHON; MELASMT-ND2NADH dehydrogenase subunit 2ETC Complex ILHONMT-ND3NADH dehydrogenase subunit 3ETC Complex ILeigh syndromeMT-ND4NADH dehydrogenase subunit 4ETC Complex ILHON; MELASMT-ND4LNADH dehydrogenase subunit 4LETC Complex ILHONMT-ND5NADH dehydrogenase subunit 5ETC Complex ILHON; Leigh syndrome; MELASMT-ND6NADH dehydrogenase subunit 6ETC Complex ILHON; MELASMT-CYBCytochrome bETC Complex IIILHON; myopathiesMT-CO1cytochrome c oxidase subunit 1ETC complex IVLHONMT-CO2Cytochrome c oxidase subunit 2ETC complex IVcytochrome c oxidase deficiencyMT-CO3Cytochrome c oxidase subunit 3ETC complex IVLHON; complex IV deficiencyMT-ATP6ATP Synthase F0 subunit 6ATP synthesis/hydrolysisLHON, Leigh syndromeMT-ATP8ATP Synthase F0 subunit 8ATP synthesis/hydrolysisLHON, Leber hereditary optic neuropathy; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MERRF, myoclonic epilepsy with ragged red fibers; NADH, reduced nicotinamide adenine dinucleotide. Open table in a new tab LHON, Leber hereditary optic neuropathy; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MERRF, myoclonic epilepsy with ragged red fibers; NADH, reduced nicotinamide adenine dinucleotide. Unlike genetic engineering of nuclear DNA, it is not currently possible to target and introduce mutations in mtDNA. Therefore, the study by Bar et al2Bär F. Bochmann W. Widok A. et al.Mitochondrial gene polymorphisms that protect mice from colitis.Gastroenterology. 2013; 145: 1055-1063Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar employs conplastic strains of mice that have the same nuclear DNA but distinct mtDNA. These mice were generated by backcrossing different strains (using the female as the donor parent to provide mtDNA) for ≥10 generations. In this way, differential responses between conplastic mice can be attributed to differences in mtDNA and can help us to understand the contributions of mtDNA mutations and altered mitochondrial functions to models of IBD. Here, Bar et al2Bär F. Bochmann W. Widok A. et al.Mitochondrial gene polymorphisms that protect mice from colitis.Gastroenterology. 2013; 145: 1055-1063Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar compare the responses of 4 conplastic strains and find that 2 strains have increased intestinal ATP levels along with increased mitochondrial oxidative phosphorylation activity and that these strains are protected from dextran sodium sulfate (DSS) and trinitrobenzene sulfonate–induced colitis. Although the 2 conplastic strains that were protected from colitis each had distinct mtDNA mutations, they shared a mutation in one of the mitochondrial tRNA genes (tRNAArg), suggesting that this mutation could account for the increased ATP, oxidative phosphorylation, and protection from colitis observed in these 2 strains. Precisely how altered mitochondrial function might lead to protection from IBD is not yet known, but the work by Bar et al2Bär F. Bochmann W. Widok A. et al.Mitochondrial gene polymorphisms that protect mice from colitis.Gastroenterology. 2013; 145: 1055-1063Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar suggests that increased respiratory capacity of mitochondria might facilitate epithelial cell proliferation and thus better barrier function. Although this field of inquiry is understudied, some lines of evidence point to a role for altered mitochondrial function in IBD. The levels of mitochondrial respiratory complex protein activity are reduced in IBD patient mucosa.3Sifroni K.G. Damiani C.R. Stoffel C. et al.Mitochondrial respiratory chain in the colonic mucosal of patients with ulcerative colitis.Mol Cell Biochem. 2010; 342: 111-115Crossref PubMed Scopus (58) Google Scholar, 4Santhanam S. Rajamanickam S. Motamarry A. et al.Mitochondrial electron transport chain complex dysfunction in the colonic mucosa in ulcerative colitis.Inflamm Bowel Dis. 2012; 18: 2158-2168Crossref PubMed Scopus (53) Google Scholar The mitochondrial translocator protein TSPO is increased in enterocytes in human IBD and after DSS treatment of rodents.5Ostuni M.A. Issop L. Peranzi G. et al.Overexpression of translocator protein in inflammatory bowel disease: potential diagnostic and treatment value.Inflamm Bowel Dis. 2010; 16: 1476-1487Crossref PubMed Scopus (25) Google Scholar Treatment with TSPO ligands modulates DSS-induced colitis and cytokine expression.5Ostuni M.A. Issop L. Peranzi G. et al.Overexpression of translocator protein in inflammatory bowel disease: potential diagnostic and treatment value.Inflamm Bowel Dis. 2010; 16: 1476-1487Crossref PubMed Scopus (25) Google Scholar Case reports of mitochondrial dysfunction in IBD have been reported. In one case, a pediatric patient with functional defects in mitochondrial respiration displaying muscle weakness, respiratory insufficiency, and seizures developed Crohn's disease that responded to anti-tumor necrosis factor (TNF) therapy.6Restivo N.L. Srivastava M.D. Schafer I.A. et al.Mitochondrial dysfunction in a patient with crohn disease: possible role in pathogenesis.J Pediatr Gastroenterol Nutr. 2004; 38: 534-538Crossref PubMed Scopus (22) Google Scholar A mutation in mtDNA was also found in a 46-year-old woman with ischemic colitis.7Hess J. Burkhard P. Morris M. et al.Ischaemic colitis due to mitochondrial cytopathy.Lancet. 1995; 346: 189-190Abstract PubMed Google Scholar Polymorphisms in mtDNA previously identified in multiple sclerosis were found to affect risk of Crohn's disease, ulcerative colitis, and other autoimmune disorders.8Yu X. Wieczorek S. Franke A. et al.Association of UCP2 -866 G/A polymorphism with chronic inflammatory diseases.Genes Immun. 2009; 10: 601-605Crossref PubMed Scopus (73) Google Scholar Mutations in mtDNA were found to be reduced in the active lesions of ulcerative colitis compared with unaffected tissues, suggesting that active inflammation may affect the relative rates of replication of mitochondria with different polymorphisms or may alter the survival or proliferation of cells with mutant mitochondria.9Fukushima K. Fiocchi C. Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients.Am J Physiol Gastrointest Liver Physiol. 2004; 286: G804-G813Crossref PubMed Scopus (26) Google Scholar Last, polymorphisms in the autophagy-related gene IRGM have been implicated in IBD. IRGM localizes to mitochondria and affects autophagy, cell death, and resistance to Mycobacterium tuberculosis.10Singh SB, Ornatowski W, Vergne I, et al. Human IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria. Nat Cell Biol;12:1154–1165.Google Scholar Bar et al2Bär F. Bochmann W. Widok A. et al.Mitochondrial gene polymorphisms that protect mice from colitis.Gastroenterology. 2013; 145: 1055-1063Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar provide evidence of increased activity of nuclear factor (NF)-κB in the intestinal epithelium of conplastic strains that were more resistant to chemically induced colitis. The role of NF-κB activity is typically to transactivate genes involved in inflammation and cell survival. However, the function of NF-κB is cell and context dependent. In innate immune cells, NF-κB activation is predominantly proinflammatory, whereas in B lymphocytes NF-κB activity is predominantly pro-survival. In the intestinal epithelium, NF-κB activity is essential to prevent TNF-induced cell death, and mice lacking NF-κB activity in intestinal epithelial cells (IECs) develop severe colitis owing to TNF-induced IEC death.11Nenci A. Becker C. Wullaert A. et al.Epithelial NEMO links innate immunity to chronic intestinal inflammation.Nature. 2007; 446: 557-561Crossref PubMed Scopus (844) Google Scholar Conversely, NF-κB activity in IECs can be proinflammatory, because constitutively active NF-κB in IECs leads to colitis, especially when accompanied by concurrent mitogen-activated protein kinase activation.12Guma M, Stepniak D, Shaked H, et al. Constitutive intestinal NF-kappaB does not trigger destructive inflammation unless accompanied by MAPK activation. J Exp Med;208:1889–1900.Google Scholar In addition, NF-κB activity in IECs can alter the course of colitis by increasing IEC tight junction integrity and by the production of antimicrobial peptides. Thus NF-κB activity in IECs is cytoprotective, but also potentially proinflammatory; therefore, context is everything when considering how NF-κB activity might impact the course of IBD. For this reason, other models of IBD, such as the IL-10-/- mouse will be important to examine to more fully understand the role of mtDNA mutations and NF-κB activity in IBD. The link between altered mitochondrial respiration and protection from colitis remains unanswered. One possibility, raised by the authors, is that altered levels of ATP impact AMPK activity in cells, leading to a potentially wide array of signaling pathways that help the cell respond to stress. Mitochondria, in addition to providing cellular supplies of energy, also participate in a wide array of cellular functions, making it difficult at present to model exactly how altered mitochondrial function could prevent inflammation. Mitochondria are platforms for innate immune signaling, including responses to viruses and for activation of the NLRP3 inflammasome.13Tait S.W. Green D.R. Mitochondria and cell signalling.J Cell Sci. 2012; 125: 807-815Crossref PubMed Scopus (282) Google Scholar These effects are mediated by a receptor called MAVS (also called CARDIF, VISA, IPS1) found on the outer mitochondrial membrane and MAVS expression and activity can be altered by the degree of mitochondrial polarization, an effect that is directly related to mitochondrial respiration.14Koshiba T, Bashiruddin N, Kawabata S. Mitochondria and antiviral innate immunity. Int J Biochem Mol Biol;2:257–262.Google Scholar Nonetheless, further exploration of the link between mtDNA mutations, altered NF-κB activity, IEC proliferation, and protection from colitis will certainly provide a rich and interesting new framework for understanding the pathogenesis of IBD. If mtDNA mutations contribute to IBD, we may be able to manipulate this effect to provide treatments for this disease. A limited number of proteins are directly encoded by mtDNA and all of them are involved in mitochondrial respiration. Known regulators that decrease mitochondrial respiration include reactive oxygen species generated by the respiratory chain, suggesting that targeted antioxidants could be beneficial to reduce chronic inflammation. Increasing the rate of mitochondrial replication or deleting defective mitochondria with agents that target mutant mtDNA in IECs might also provide some benefits in IBD. Defective mitochondria are cleared from cells by a specialized form of autophagy, called mitophagy, and increasing this activity might help to improve the overall mitochondrial activity of cells. This might be of particular interest given that IRGM, which is genetically associated with IBD, is a mitochondrial protein involved in autophagy. One interesting question is whether and how current useful therapies might act in part by altering mitochondrial function, or whether mtDNA mutations impact the response of patients to certain therapies. For example, it would not be surprising to learn that azathioprine or 6-mercaptopurine impact mitochondrial function and that such an effect could contribute to the efficacy of these drugs. Because defective mitochondrial function has been implicated in many human disorders, including Parkinson disease, type 2 diabetes, and other age-related diseases, we should be cognizant of the work by our scientific and clinical colleagues in those research areas to better develop new therapies and understanding of the contribution of mtDNA mutations to IBD. Mitochondrial Gene Polymorphisms That Protect Mice From ColitisGastroenterologyVol. 145Issue 5PreviewDysregulated energy homeostasis in the intestinal mucosa frequently is observed in patients with ulcerative colitis (UC). Intestinal tissues from these patients have reduced activity of the mitochondrial oxidative phosphorylation (OXPHOS) complex, so mitochondrial dysfunction could contribute to the pathogenesis of UC. However, little is known about the mechanisms by which OXPHOS activity could be altered. We used conplastic mice, which have identical nuclear but different mitochondrial genomes, to investigate activities of the OXPHOS complex. Full-Text PDF Covering the CoverGastroenterologyVol. 145Issue 5PreviewEndoscopy plays an essential role in the management of patients with inflammatory bowel disease and in the evaluation of the efficacy of new treatment modalities. Interobserver variation in the assessment of endoscopic severity of disease in patients with ulcerative colitis and patients with Crohn's disease has led to the development of several activity indices, including the Mayo Clinic Index, the Ulcerative Colitis Disease Activity Index, the Ulcerative Colitis Index of Severity (UCEIS), and the Crohn's Disease Endoscopic Index of Severity (CDEIS), and the Simplified Endoscopic Score for Crohn's Disease (SES-CD), respectively. Full-Text PDF" @default.
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• W2004709337 title "The Other Genome: Mitochondrial DNA and Protection From Experimental Colitis" @default.
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