The mitochondrial peptidase IMMP2L has been highly conserved, from E. coli to human, commensurate with its key roles in mitochondrial and cellular homeostasis, metabolism and mitochondrial dynamics. We previously reported how the loss of Immp2l activity in mice acts as an antioxidant by decreasing the level of reactive oxygen species (ROS), cellular oxygen consumption, mitochondrial respiration, nonmitochondrial respiration, body size and organ size in association with antioxidant hyperdopaminergic behavioural phenotypes. We now report that the Immp2lKD-/-KO mouse displays stereotypic autism-like behaviour and as such represents an excellent model to investigate the repeated linkage of IMMP2L with autism inheritance and its wider role in mitochondrial structure and function. Furthermore, we report increased levels of the reduced form of glutathione (GSH) in the brain of the Immp2lKD -/- KO mouse consistent with the decreases observed in ROS. In addition, electron microscopy analysis across the medial prefrontal cortex (mPFC) of the Immp2lKD-/-KO mouse revealed an increase in the number of mitochondria, a total loss of all larger mitochondria and a substantial decrease in both the mean size of mitochondria (p=10-34) and the overall mitochondrial mass. We also observed large and significant increases in the level of NAD+ and NADH and in the NAD+/NADH ratio in the PFC of these mice. A similar increase in NAD+ biosynthesis was observed in primary MEF cell lines derived from the Immp2lKD -/- KO mouse. There was a decrease in the level of acetylation of histones H3 and H4 at the promoter of the Dat1dopamine reuptake transporter gene in the prefrontal cortex of these mice consistent with decreased expression of Dat1 and the increased behavioural sensitivity of these mice to dexamphetamine and stereotypic-like behaviour. The level of acetylation of histone H3 was also decreased at the tyrosine hydroxylase (Th) gene promoter which is regulated by the NAD+ activated deacetylase Sirt1. Sirt1 also deacetylates/activates PGC-1⍺, the master regulator of mitochondrial biosynthesis and dynamics. Together, these findings indicate a shared pathway for the increased biosynthesis of NAD+, changed behaviour and decreased size of mitochondria in the Immp2lKD-/-KO mouse. These findings identify a major role for Immp2l in the brain where it regulates the level of GSH and ROS and enhances glycolysis, mitochondrial respiration, mitochondrial dynamics, metabolism, NAD+ biosynthesis, histone acetylation levels at dopamine gene promoters and behaviour. This study identifies a strong connection between metabolism and behaviour and is the first to positively associate Immp2l with variations in organ size, body size, mitochondrial size and cellular oxygen consumption. The Immp2lKD-/-KO mouse model pathway appears to run in reverse to the dopamine mediated ‘reward circuitry’ model of autism put forward by Dichter et al. which proposes ‘a reduction in dopamine release in the prefrontal cortex leading to hypoactivation of the mesocorticolimbic reward system’.
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