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

J Neurosci. 2019 May 1;39(18):3561-3581. doi: 10.1523/JNEUROSCI.1983-18.2019. Epub 2019 Mar 4.


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 cell-specific manner.SIGNIFICANCE STATEMENT We address the central question of how to comprehensively define molecular mechanisms of the most prevalent and penetrant microdeletion associated with neurodevelopmental disorders, the 22q11.2 microdeletion syndrome. This complex mutation reduces gene dosage of ∼63 genes in humans. We describe a disruption of the mitoproteome in 22q11.2 patients and brains of a 22q11.2 mouse model. In particular, we identify a network of inner mitochondrial membrane transporters as a hub required for synapse function. Our findings suggest that mitochondrial composition and function modulate the risk of neurodevelopmental disorders, such as schizophrenia.

Keywords: 22q11.2 microdeletion; SLC25A1; SLC25A4; mitochondria; schizophrenia; synapse.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 22q11 Deletion Syndrome / metabolism*
  • Adenine Nucleotide Translocator 1 / metabolism
  • Animals
  • Behavior, Animal
  • Brain / metabolism*
  • Cell Line
  • Chromosome Deletion
  • Chromosomes, Human, Pair 22 / metabolism
  • Drosophila
  • Female
  • Fibroblasts / metabolism
  • Humans
  • Male
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / metabolism
  • Neurons / metabolism*
  • Organic Anion Transporters / metabolism
  • Proteome
  • Schizophrenia / metabolism
  • Synapses / metabolism*


  • Adenine Nucleotide Translocator 1
  • Mitochondrial Proteins
  • Organic Anion Transporters
  • Proteome
  • SLC25A4 protein, human
  • Slc25a1 protein, human

Supplementary concepts

  • Chromosome 22, microdeletion 22 q11