title: Role of MHC class I in immune surveillance of mitochondrial DNA integrity.
abstract: Mitochondrial DNA is subject to increased rates of mutations due to its proximity to the source of reactive oxygen species. Here we show that increased MHC class I (MHC I) expression serves to alert the immune system to cells with mitochondrial mutations. MHC I is overexpressed in fibroblasts with mitochondrial dysfunction from patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes and in lymphocytes from purine nucleoside phosphorylase-deficient immune-deficient mice with mitochondrial DNA deletions. Consistent with a role of MHC I in the elimination of cells containing mitochondrial DNA mutations, mice deficient in MHC I accumulate mitochondrial DNA deletions in various tissues. These observations in both mice and humans suggest a role for the immune system in preventing reversion of mitochondrial DNA back into a parasitic state following deleterious mutations affecting mitochondrial oxidative phosphorylation.
authors.affiliation: Division of Immunology and Allergy, Department of Pediatrics and Immunology, Research Institute, University of Toronto and Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Gu
authors.forename: Chunjie
authors.initials: C
authors.lastname: Wang
authors.forename: Chaim M
authors.initials: CM
authors.lastname: Roifman
authors.forename: Amos
authors.initials: A
authors.lastname: Cohen
mesh_terms: D000818:Animals; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D003848:Deoxyguanine Nucleotides / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D007157:Immunologic Surveillance / Q000235:genetics; D007371:Interferon-gamma / Q000494:pharmacology; D017241:MELAS Syndrome / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012516:Osteosarcoma / Q000201:enzymology / Q000235:genetics; D010766:Phosphorylation; D011683:Purine-Nucleoside Phosphorylase / Q000172:deficiency / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D003848:Deoxyguanine Nucleotides; D015395:Histocompatibility Antigens Class I; D017382:Reactive Oxygen Species; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D007371:Interferon-gamma; C029603:deoxyguanosine triphosphate; D011683:Purine-Nucleoside Phosphorylase