Autism candidate gene rbm-26 ( RBM26/27 ) regulates MALSU-1 to protect against mitochondrial dysfunction during axon development.

Mitochondrial dysfunction is thought to be a key component of neurodevelopmental disorders such as autism, intellectual disability, and ADHD. However, little is known about the molecular mechanisms that protect against mitochondrial dysfunction during neurodevelopment. Here, we address this question through the investigation of rbm-26 , the C. elegans ortholog of the RBM27 autism candidate gene, which encodes an RNA-binding protein whose role in neurons is unknown. We report that RBM-26 (RBM26/27) protects against neurodevelopmental defects by negatively regulating expression of the MALSU-1 mitoribosomal assembly factor. Autism-associated missense variants in RBM-26 cause a sharp decrease in RBM-26 protein expression along with neurodevelopmental defects, including errors in axon targeting and axon degeneration. Using an unbiased screen, we identified the mRNA for the MALSU-1 mitoribosomal assembly factor as a binding partner for RBM-26. RBM-26 negatively regulates the expression of malsu-1 mRNA and MALSU-1 protein, and genetic analysis indicates that this interaction is required to protect against neurodevelopmental defects. Moreover, biochemical evidence suggests that excess levels of MALSU-1 disrupt the biogenesis of mitoribosomes in rbm-26 mutants. These observations reveal a mechanism that can protect mitochochondrial function to prevent neurodevelopmental defects and suggest that disruptions in this process can cause neurodevelopmental disorders.