Mitochondrial ATP synthase 8 single-nucleotide polymorphism affects oxidative stress and survival of mice

Abstract

Single-nucleotide polymorphisms in mitochondrial DNA (mtDNA) encoded genes of respiratory chain complexes are known to be associated with severe diseases and life-threatening syndromes. In the assembly of the ATP synthase, the enzyme that in the final steps of oxidative phosphorylation generates ATP from ADP and inorganic phosphate, two subunits (ATP6 and ATP8) are mtDNA-encoded. In our study, we investigated the impact of a single-nucleotide polymorphism in MT-ATP8 with respect to memory function in a preclinical model. Here, we have employed two conplastic mouse strains. The mouse strain C57BL/6 J-mt^AKR/J served as a control with wild-type sequence in MT-ATP8, while C57BL/6 J-mt^FVB/NJ exhibited an m.7778G > T transversion. Using two age groups (3 months and 24 months), levels of reactive oxygen species (ROS), spatial learning in the Morris-Water-Maze, and long-term potentiation were assessed. Immunohistologically, the expressions of NeuN and GFAP were quantified. Additionally, the lifespan of both strains was registered. In comparison to young C57BL/6 J-mt^FVB/NJ mice, aged animals had higher ROS levels in the hippocampus. A decreased NeuN/GFAP level was found in C57BL/6 J-mt^FVB/NJ mice as well as in old animals of the control strain. Aged animals performed worse in the swimming trials, but no significant differences between both strains were detected. The long-term potentiation recordings revealed reduced synaptic plasticity in young C57BL/6 J-mt^FVB/NJ mice. Interestingly, C57BL/6 J-mt^FVB/NJ mice presented an extended lifespan compared to animals of the control strain. Together, our data suggest a minor impact of a single-nucleotide polymorphism in MT-ATP8 on spatial learning and oxidative stress depending on the neuronal tissue. In line with the concept of mitohormesis, our findings may be linked to the longevity of mice harbouring single-nucleotide polymorphisms.

Keywords: ATP synthase; Ageing; Cognition; Conplastic mouse strains; Lifespan; Long-term potentiation; MT-ATP8; MtDNA variants; Oxidative stress; Single-nucleotide polymorphism.