Somatic mutations in the mitochondria of rheumatoid arthritis synoviocytes |
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Authors: | Email author" target="_blank">Tanya?R?Da SylvaEmail author Alison?Connor Yvonne?Mburu Edward?Keystone Gillian?E?Wu |
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Institution: | (1) Department of Biology, York University, Toronto, Ontario, Canada;(2) The Wellesley Toronto Arthritis and Immune Disorder Research Centre, University Health Network, Toronto, Ontario, Canada;(3) Department of Medicine, University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada |
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Abstract: | Somatic mutations have a role in the pathogenesis of a number of diseases, particularly cancers. Here we present data supporting
a role of mitochondrial somatic mutations in an autoimmune disease, rheumatoid arthritis (RA). RA is a complex, multifactorial
disease with a number of predisposition traits, including major histocompatibility complex (MHC) type and early bacterial
infection in the joint. Somatic mutations in mitochondrial peptides displayed by MHCs may be recognized as non-self, furthering
the destructive immune infiltration of the RA joint. Because many bacterial proteins have mitochondrial homologues, the immune
system may be primed against these altered peptides if they mimic bacterial homologues. In addition, somatic mutations may
be influencing cellular function, aiding in the acquirement of transformed properties of RA synoviocytes. To test the hypothesis
that mutations in mitochondrial DNA (mtDNA) are associated with RA, we focused on the MT-ND1 gene for mitochondrially encoded NADH dehydrogenase 1 (subunit one of complex I – NADH dehydrogenase) of synoviocyte mitochondria
from RA patients, using tissue from osteoarthritis (OA) patients for controls. We identified the mutational burden and amino
acid changes in potential epitope regions in the two patient groups. RA synoviocyte mtDNA had about twice the number of mutations
as the OA group. Furthermore, some of these changes had resulted in potential non-self MHC peptide epitopes. These results
provide evidence for a new role for somatic mutations in mtDNA in RA and predict a role in other diseases. |
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