title: The mtDNA nt7778 G/T polymorphism affects autoimmune diseases and reproductive performance in the mouse.
abstract: 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.
authors.affiliation: Section of Immunogenetics, University of Rostock, Rostock, Germany.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Yu
authors.forename: Lena
authors.initials: L
authors.lastname: Wester-Rosenlöf
authors.forename: Ulrike
authors.initials: U
authors.lastname: Gimsa
authors.forename: Stephanie-Anna
authors.initials: SA
authors.lastname: Holzhueter
authors.forename: Andreia
authors.initials: A
authors.lastname: Marques
authors.forename: Ludwig
authors.initials: L
authors.lastname: Jonas
authors.forename: Kristin
authors.initials: K
authors.lastname: Hagenow
authors.forename: Manfred
authors.initials: M
authors.lastname: Kunz
authors.forename: Horst
authors.initials: H
authors.lastname: Nizze
authors.forename: Markus
authors.initials: M
authors.lastname: Tiedge
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
authors.forename: Saleh M
authors.initials: SM
authors.lastname: Ibrahim
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D054629:Genome, Mitochondrial; D006861:Hydrogen Peroxide / Q000378:metabolism; D007247:Infertility, Female / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000201:enzymology*; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics*; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D012098:Reproduction / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D006861:Hydrogen Peroxide; D025261:Mitochondrial Proton-Translocating ATPases; C546989:mt-Atp8 protein, mouse