Mitochondrial proteostasis requires genes encoded in a neurodevelopmental syndrome locus

Avanti Gokhale, Chelsea E. Lee, Stephanie A. Zlatic, Amanda A.H. Freeman, Nicole Shearing, Cortnie Hartwig, Oluwaseun Ogunbona, Julia L. Bassell, Meghan E. Wynne, Erica Werner, Chongchong Xu, Zhexing Wen, Duc Duong, Nicholas T. Seyfried, Carrie E. Bearden, Viktor János Oláh, Matthew J.M. Rowan, Jill R. Glausier, David A. Lewis, Victor Faundez

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Eukaryotic cells maintain proteostasis through mechanisms that require cytoplasmic and mitochondrial translation. Genetic defects affecting cytoplasmic translation perturb synapse development, neurotransmission, and are causative of neurodevelopmental disorders, such as Fragile X syndrome. In contrast, there is little indication that mitochondrial proteostasis, either in the form of mitochondrial protein translation and/or degradation, is required for synapse development and function. Here we focus on two genes deleted in a recurrent copy number variation causing neurodevelopmental disorders, the 22q11.2 microdeletion syndrome. We demonstrate that SLC25A1 and MRPL40, two genes present in the microdeleted segment and whose products localize to mitochondria, interact and are necessary for mitochondrial ribosomal integrity and proteostasis. Our Drosophila studies show that mitochondrial ribosome function is necessary for synapse neurodevelopment, function, and behavior. We propose that mitochondrial proteostasis perturbations, either by genetic or environmental factors, are a pathogenic mechanism for neurodevelopmental disorders.

Original languageEnglish (US)
Pages (from-to)6596-6616
Number of pages21
JournalJournal of Neuroscience
Issue number31
StatePublished - Aug 4 2021
Externally publishedYes


  • 22q11.2
  • CNV
  • Mitochondria
  • Neurodevelopmental
  • Protein synthesis
  • Schizophrenia
  • Synapse

ASJC Scopus subject areas

  • General Neuroscience


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