Role of MHC class I in immune surveillance of mitochondrial DNA integrity.
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.
Gu
Yiping
Y
Division of Immunology and Allergy, Department of Pediatrics and Immunology, Research Institute, University of Toronto and Hospital for Sick Children, Toronto, Ontario, Canada.
Wang
Chunjie
C
Roifman
Chaim M
CM
Cohen
Amos
A
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
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