Mitochondrial deficits in human iPSC-derived neurons from patients with 22q11.2 deletion syndrome and schizophrenia

We find significant reductions of ATP levels that appear to be secondary to reduced activity in oxidative phosphorylation complexes I and IV

Jianping Li; Sean K. Ryan; Erik Deboer; Kieona Cook; Shane Fitzgerald; Herbert M. Lachman; Douglas C. Wallace; Ethan M. Goldberg; Stewart A. Anderson

2019

Scholarcy highlights

  • Schizophrenia is a heterogeneous disorder generally characterized by adolescent onset of psychosis together with deteriorations of social and cognitive functioning
  • Since nine of the roughly 45 genes deleted in 22q11DS generate proteins affect mitochondrial function, we examined this function in induced pluripotent stem cells-derived neurons
  • We found that ATP levels were reduced in iPSC-derived neurons from patients with 22q11DS and SZ, a phenotype that appears to be caused primarily by reduced activity of complexes I and IV
  • Since complexes I and IV have the highest number of mitochondrial-encoded proteins, these findings raised the possibility that the 22q11DS is associated with reduced neuronal protein synthesis, an idea supported by the presence of MRPL40 in the deleted region
  • MRPL40 hemizygous neurons have normal levels of mitochondria proteins encoded by nuclear genes, but decreased levels of proteins encoded by the mitochondrial DNA, decreases in electron transport chain complexes I and IV activities, and decreased ATP level
  • We conclude that hemizygosity at 22q11.2 is associated with decreased neuronal ATP levels, and that this phenotype is most likely related to decreased mitochondrial protein synthesis
  • While the lack of neuronal phenotypes such as input synaptogenesis and electrophysiological measures is disappointing, since such phenotypes could secondarily influence mitochondrial function, the high similarities in properties between iPSC lines to neurons from the 22q11DS and SZ and control groups strengthens our confidence that the mitochondria phenotypes themselves are not epiphenomena

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