The mtDNA nt7778 G/T polymorphism affects autoimmune diseases and reproductive performance in the mouse
| Autor: | Ulrike Gimsa, Ludwig Jonas, Horst Nizze, Lena Wester-Rosenlöf, Andreia de Castro Marques, Manfred Kunz, Saleh M. Ibrahim, Kristin Hagenow, Markus Tiedge, Xinhua Yu, Stephanie-Anna Holzhueter, Rikard Holmdahl |
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| Rok vydání: | 2009 |
| Předmět: |
Mitochondrial DNA
Molecular Sequence Data Arthritis Oxidative phosphorylation Mitochondrion Biology medicine.disease_cause DNA Mitochondrial Autoimmunity Autoimmune Diseases Mice Genetics medicine Animals Amino Acid Sequence Molecular Biology Genetics (clinical) Autoimmune pancreatitis Autoimmune disease Polymorphism Genetic ATP synthase Reproduction General Medicine Hydrogen Peroxide Mitochondrial Proton-Translocating ATPases medicine.disease Mice Mutant Strains Mitochondria Genome Mitochondrial biology.protein Female Infertility Female |
| Zdroj: | Human molecular genetics. 18(24) |
| ISSN: | 1460-2083 |
| Popis: | Mitochondria are organelles of all nucleated cells, and variations in mtDNA sequence affect a wide spectrum of human diseases. However, animal models for mtDNA-associated diseases are rare, making it challenging to explore mechanisms underlying the contribution of mitochondria. Here, we identify a polymorphism in the mitochondrial genome, G-to-T at position 7778, which results in an aspartic acid-to-tyrosine (D-Y) substitution in the fifth amino acid of the highly conserved N-terminus of ATP synthase 8 (ATP8). Using a series of conplastic strains we show that this polymorphism increases susceptibility to multiple autoimmune diseases, including collagen-induced arthritis, autoimmune diabetes, nephritis and autoimmune pancreatitis. In addition, it impairs reproductive performance in females, but only in the MRL/MpJ strain. We also demonstrate that the mtAtp8 polymorphism alters mitochondrial performance, increasing H(2)O(2) production and affecting mitochondrial structure. Functional analysis reveals that the polymorphism increase the CD4 T cell adaptive potential to an oxidative phosphorylation impaired condition. Our findings provide direct experimental evidence for the role of mitochondria in autoimmunity and reproduction. |
| Databáze: | OpenAIRE |
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