A cleaved cytosolic FOXG1 promotes excitatory neurogenesis by modulation of mitochondrial translation – a new therapeutic target for brain disorders

Modulation of mitochondrial function is at the core of cell fate decisions and tissue homeostasis, yet the mechanisms that govern their activity are not understood. Here, we provide evidence that mitochondrial activity is controlled in a tissue-specific manner through a non-canonical cytoplasmic function of the transcription factor FOXG1. Using zebrafish and human models of the neurodevelopmental disorder, FOXG1 Syndrome, we found that FOXG1 mutations inducing a premature stop codon unexpectedly lead to the production of a short C-terminal peptide. The expression of this truncated protein is responsible for an excess of excitatory neurons and a structural, functional, and translational mitochondrial phenotype in mutants. We demonstrate that this activity is a gain of function, normally carried out by a cleavage product in wildtype. Both peptides promote the translation of mitochondrially-encoded transcripts, are preferentially transported to the mitochondria, and interact with mito-ribosomal proteins. These findings unveil a mechanism that integrates cell fate decisions with metabolic output. Adjusting the dosage of the mutant peptide rescues aspects of FOXG1 Syndrome, offering a new therapeutic avenue for the treatment of disorders involving mitochondrial dysfunctions.