Improvements of autism-like behaviors but limited effects on immune cell metabolism after mitochondrial replacement in BTBR T Itpr3/J mice

Mitochondria-mediated metabolic impairment and dysfunction are highly related with autism. Herein, the mitochondria-mediated metabolism of BTBR T+Itpr3tf/J (BTBR) mice with autistic-like behaviors was investigated. A new BTBR-mtB6 strain generated by deriving BTBR mice with C57BL/6J (B6) mitochondria was used to determine the role of the mitochondrial genome. The BTBR-mtB6 mice had improved social behaviors, higher levels of glutamate and astrocytes in the brain and less neuroinflammation than the BTBR mice; however, many of the metabolic parameters of BTBR mice such as enhanced fatty acid β-oxidation and lower glycolysis and glutaminolysis in immune cells compared to B6 mice were not or only partial improved in the BTBR-mtB6 strain. The BTBR and BTBR-mtB6 mice also had equivalent ETC (enhanced electron transport chain) activity of mitochondria, with an increase of reactive oxygen species (ROS) and decreased mitochondrial membrane potential compared to the B6 mice. The results suggest that the mitochondrial replacement with its metabolic alterations affect brain functions more than peripheral immune cell activities.