Systems Analysis of the 22q11.2 Microdeletion Syndrome Converges on a Mitochondrial Interactome Necessary for Synapse Function and Behavior

Abstract

Neurodevelopmental disorders offer insight into synaptic mechanisms. To unbiasedly uncover these mechanisms, we studied the 22q11.2 syndrome, a recurrent copy number variant, which is the highest schizophrenia genetic risk factor. We quantified the proteomes of 22q11.2 mutant human fibroblasts from both sexes and mouse brains carrying a 22q11.2-like defect, Df(16)A ؉/؊ . Molecular ontologies defined mitochondrial compartments and pathways as some of top ranked categories. In particular, we identified perturbations in the SLC25A1-SLC25A4 mitochondrial transporter interactome as associated with the 22q11.2 genetic defect. Expression of SLC25A1-SLC25A4 interactome components was affected in neuronal cells from schizophrenia patients. Furthermore, hemideficiency of the Drosophila SLC25A1 or SLC25A4 orthologues, dSLC25A1-sea and dSLC25A4-sesB, affected synapse morphology, neurotransmission, plasticity, and sleep patterns. Our findings indicate that synapses are sensitive to partial loss of function of mitochondrial solute transporters. We propose that mitoproteomes regulate synapse development and function in normal and pathological conditions in a cellspecific manner.

Abnormalities of synaptic mitochondria in autism spectrum disorder and related neurodevelopmental disorders

“…This study highlights the relevance of mitochondria in synapses and their implications in normal and neuronal disease states and emphasizes existing differences in the mitochondrial population depending on brain regions. Others reported alterations in the mitochondrial proteome of the hippocampus and prefrontal cortex in a 22q11.2 microdeletion mouse model [ 123 ]. Specifically, the mitochondrial transporters encoded by Slc25a1 - Slc25a4 appear to play a significant role in synapse formation.…”

“…al 2019 [ 122 ] Absence of cristae, increased ROS production LgDel 22q11 mice Cortex (layer 2/3) Gokhale et. al 2019 [ 123 ] Mitochondrial proteome affected Df(16)A +/- mice Hippocampus, PFC Kriaucionis et. al 2006 [ 145 ] Increased respiration Mecp2 -KO mice Mitochondria isolated from whole brains Urdinguio et.…”

Tourette Syndrome Risk Genes Regulate Mitochondrial Dynamics, Structure, and Function

“…The exact mitochondrial mechanism implicated in GTS has not been identified as there is no evidence of mitochondrial mediated increases in ROS or ROS related neurodegeneration in GTS as is commonly the case in neurodegenerative disorders. A deficit in neuronal energy supply during development is one possible contributing factor in the etiology of GTS, however, the waning of tic severity in GTS over time appears more consistent with a deficit in neurotransmission possibly compensated for at later ages (185)(186)(187)(188)(189). We have no nonmolecular evidence of a mitochondrial pathway to GTS at this time, notwithstanding, this is the 1st study to report a mitochondrial pathway to GTS and we are confident it will not be the last.…”

Using induced pluripotent stem cells to investigate human neuronal phenotypes in 1q21.1 deletion and duplication syndrome

“…Several cellular studies looking at cellular phenotypes of other CNVs such as 2p16.3/NRXN1, 15q13.3, 16p11.2, 22q11.21 have also shown synaptic dysfunction [39][40][41] . Therefore, cellular dysfunction associated with CNVs (linked to psychiatric disorders) is likely to converge on deficiencies in synaptic machinery.…”