Role of MHC class I in immune surveillance of mitochondrial DNA integrity

J Immunol. 2003 Apr 1;170(7):3603-7. doi: 10.4049/jimmunol.170.7.3603.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA Damage
  • DNA, Mitochondrial / genetics
  • DNA, Mitochondrial / metabolism*
  • DNA-Binding Proteins / metabolism
  • Deoxyguanine Nucleotides / genetics
  • Deoxyguanine Nucleotides / metabolism
  • Fibroblasts / immunology
  • Fibroblasts / metabolism
  • Histocompatibility Antigens Class I / biosynthesis
  • Histocompatibility Antigens Class I / physiology*
  • Humans
  • Immunologic Deficiency Syndromes / enzymology
  • Immunologic Deficiency Syndromes / genetics
  • Immunologic Deficiency Syndromes / immunology
  • Immunologic Surveillance* / genetics
  • Interferon-gamma / pharmacology
  • MELAS Syndrome / immunology
  • MELAS Syndrome / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Osteosarcoma / enzymology
  • Osteosarcoma / genetics
  • Phosphorylation
  • Purine-Nucleoside Phosphorylase / deficiency
  • Purine-Nucleoside Phosphorylase / genetics
  • Reactive Oxygen Species / metabolism
  • STAT1 Transcription Factor
  • Trans-Activators / metabolism
  • Tumor Cells, Cultured

Substances

  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • Deoxyguanine Nucleotides
  • Histocompatibility Antigens Class I
  • Reactive Oxygen Species
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Stat1 protein, mouse
  • Trans-Activators
  • Interferon-gamma
  • deoxyguanosine triphosphate
  • Purine-Nucleoside Phosphorylase