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.

Polymorphism in Murine mtATP8 Gene Correlates with Decreased Reactive Oxygen Species in Aging Hematopoietic Cells

“…They reported a higher ROS production in spleen cells but no impaired mitochondrial respiration in 3-to 6-month-old animals (19). These findings differ from ours as we observed lower levels of ROS in BMC in the mtFVB strain.…”

“…The C57BL/6-mt FVB/NJ (mtFVB) strain harbors the nt7778G/T polymorphism, while the control C57BL/6-mt AKR/J (mtAKR) strain is unaltered at this position. The replacement of aspartic acid, which lacks an aromatic group with tyrosine at the fifth position of the highly-conserved Nterminal region, is important for proper complex V assembly (19). Due to the proton channeling function of subunit F O , we hypothesize that the polymorphism will alter the transport of protons by complex V and, therefore, the generation of the proton gradient.…”

“…It would, thus, impact the whole respiratory chain, influencing ROS and ATP production. Recently, the impact of the nt7778 G/T polymorphism on cell function has been studied in different tissues (19)(20)(21)(22), as well as its effects on anxiety and stress reactivity (23,24).…”

Polymorphisms in the mitochondrially encoded ATP synthase 8 gene are associated with susceptibility to bullous pemphigoid in the German population

“…One of the subunits of complex V, ATP synthase protein 8 (or A6L), is encoded by the mitochondrially encoded ATP synthase 8 gene (MT-ATP8) (2). Our group and others have experimentally demonstrated that a mutation in MT-ATP8 increases disease severity via increased ROS levels in several autoimmune disease models, including collagen-induced arthritis and lupus (7). Interestingly, a mutation in MT-ATP8 was found in a patient with multiple sclerosis (s2).…”

Beyond retrograde and anterograde signaling: Mitochondrial - nuclear interactions as a means for evolutionary adaptation and contemporary disease susceptibility

“…However, these studies by necessity have had to utilize transformed or immortalized cell lines and therefore do not exactly represent in vivo circumstances. Studies utilizing conplastic strains of mice (mice having different nuclear and mitochondrial genetic backgrounds, generated by breeding two different strains to generate F 1 females and backcrossing them and subsequent filial female generations onto the nuclear background of the paternal strain), suggest that mtDNA background does influence aspects of cognition, behavior, reproductive behavior, and susceptibility to autoimmune disease [43][44][45][46]. A potential issue with even this approach is that if the mtDNA alters organelle economy (bioenergetics) which can affect numerous nuclear genes, the mtDNA may also play a role in modulating nuclear gene expression and perhaps play a role in allelic segregation and assortment during meiosis.…”