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, Saleh M. Ibrahim*

*Corresponding author for this work
34 Citations (Scopus)


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.

Original languageEnglish
JournalHuman Molecular Genetics
Issue number24
Pages (from-to)4689-4698
Number of pages10
Publication statusPublished - 26.11.2009

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)


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