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Identifying and targeting abnormal mitochondrial localization associated with psychosis.

Marzieh Haghighi1, Donna McPhie2, Mohammad Rohban1

  • 1Imaging Platform, Broad Institute of MIT and Harvard, Cambridge MA USA 02142.

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Novel cell-based assays can identify new psychiatric treatments. Skin cells from patients with psychosis showed altered mitochondria positioning, a metric useful for screening drug candidates and genetic targets.

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Area of Science:

  • Cell biology
  • Neuroscience
  • Pharmacology

Background:

  • Novel therapeutics are crucial for psychiatric conditions.
  • Cell-based assays offer a method to identify therapeutic candidates.
  • Understanding cellular phenotypes in psychiatric disorders is key.

Purpose of the Study:

  • To develop and validate a cell-based assay for identifying novel psychiatric therapeutics.
  • To investigate mitochondrial positioning in peripheral cells of psychiatric patients.
  • To screen for compounds and genes impacting the identified cellular phenotype.

Main Methods:

  • Imaging peripheral skin fibroblasts from 168 psychiatric patients.
  • Staining cells for DNA, actin, and mitochondria.
  • Quantifying mitochondrial distance from the cell border.
  • Querying cell databases for compounds/genes affecting the phenotype.

Main Results:

  • Mitochondria were significantly farther from the cell border in patients experiencing psychosis (schizophrenia, bipolar disorder, schizoaffective disorder).
  • A non-significant trend for reversed mitochondrial positioning was observed in major depression.
  • Several compounds and genes were identified that modulate the psychosis-associated mitochondrial phenotype.

Conclusions:

  • A novel cell-based assay using mitochondrial positioning shows promise for psychiatric drug discovery.
  • This assay can be used for virtual and physical screening of therapeutic candidates.
  • The findings support the development of novel mechanism therapeutics for psychiatric conditions.