Journal Article

The mtDNA nt7778 G/T polymorphism affects autoimmune diseases and reproductive performance in the mouse

Xinhua Yu, Lena Wester-Rosenlöf, Ulrike Gimsa, Stephanie-Anna Holzhueter, Andreia Marques, Ludwig Jonas, Kristin Hagenow, Manfred Kunz, Horst Nizze, Markus Tiedge, Rikard Holmdahl and Saleh M. Ibrahim

in Human Molecular Genetics

Volume 18, issue 24, pages 4689-4698
Published in print December 2009 | ISSN: 0964-6906
Published online September 2009 | e-ISSN: 1460-2083 | DOI:
The mtDNA nt7778 G/T polymorphism affects autoimmune diseases and reproductive performance in the mouse

Show Summary Details


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 H2O2 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.

Journal Article.  5068 words.  Illustrated.

Subjects: Genetics and Genomics

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