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bioRxiv · 10.1101/2024.08.13.607559

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

Bruce, H.·Halpern, M. E.·Monfries, C.·Suleyman, O.·Hamid, F.·Houart, C.
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Abstract

The modulation of mitochondrial function is core to cell fate decisions and tissue homeostasis, yet the mechanisms regulating these processes remain poorly understood. Here, we demonstrate that mitochondrial OXPHOS activity is controlled in a tissue-specific manner through a non-canonical cytoplasmic function of the transcription factor FOXG1. A temporally regulated short cytoplasmic FOXG1 interacts with mitochondrial ribosomal proteins and enhances translation of mt-DNA-encoded OXPHOS proteins. Zebrafish and human models of early nonsense FOXG1 syndrome mutations unexpectedly produce a short C-terminal peptide. Expression of this truncated protein drives an overproduction of excitatory neurons and induces a structural, functional, and translational phenotype in mutant mitochondria. We demonstrate that this activity is a gain of function, normally carried out by a cleaved FOXG1 in wildtype. Both normal and mutant peptides are transported to the mitochondria, interact with mito-ribosomal proteins to enhance translation, thereby stimulating neurogenesis. Adjusting the dosage of the mutant peptide rescues the excitatory aspect of the FOXG1 syndrome. Our study demonstrates a novel role for cytoplasmic Foxg1 in promoting neurogenesis via the tuning of mitochondrial translation and provides the first evidence for direct tissue-specific control of OXPHOS activity. This study opens a novel therapeutic avenue for the treatment of disorders associated with mitochondrial hypoactivity. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/607559v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1b8806forg.highwire.dtl.DTLVardef@1f81e3forg.highwire.dtl.DTLVardef@89d9e1org.highwire.dtl.DTLVardef@3f7a72_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Bruce, H., Halpern, M. E., Monfries, C., Suleyman, O., Hamid, F., Houart, C.. 2024-08-13. A cleaved cytosolic FOXG1 promotes excitatory neurogenesis by modulation of mitochondrial translation - a new therapeutic target for brain disorders.. https://doi.org/10.1101/2024.08.13.607559

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