Non-coding exon splicing orchestrates tissue-specific expression of two functionally distinct mitochondrial isoforms of Mitofusin 2

DAVID, C.; BARSA, C.; EVAIN, C.; KRÜGER, A.; PAPIN, M.; BERNADET, R.; DURANTHON, G.; MOLINIE, T.; COUGOUILLES, E.; DOMPIERRE, J.; ROJO, M.; LEFEVRE, A.; PASDOIS, P.; RORBACH, J.; HABERMANN, B. H.; MOURIER, A.

doi:10.1101/2025.09.26.678759

bioRxiv · 10.1101/2025.09.26.678759

Non-coding exon splicing orchestrates tissue-specific expression of two functionally distinct mitochondrial isoforms of Mitofusin 2

DAVID, C.·BARSA, C.·EVAIN, C.·KRÜGER, A.·PAPIN, M.·BERNADET, R.·DURANTHON, G.·MOLINIE, T.·COUGOUILLES, E.·DOMPIERRE, J.·ROJO, M.·LEFEVRE, A.·PASDOIS, P.·RORBACH, J.·HABERMANN, B. H.·MOURIER, A.

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Abstract

In mammals, outer mitochondrial membrane fusion controls mitochondrial network morphology, promotes subcellular trafficking and ensures proper mitochondrial content mixing. This process is controlled by two homologous dynamin related proteins, MFN1 and MFN2, which are ubiquitously expressed across tissues. Intriguingly, in humans, loss of function of MFN2 is responsible for the Charcot-Marie-Tooth type 2A neuropathy, whereas no pathogenic mutations are known in MFN1. Here, we report a short isoform of MFN2 that is generated by an evolutionary conserved alternative translation initiation site. This short mitochondrial MFN2 isoform (S-MFN2) is highly abundant in the mouse brain and its tissue-specific expression is controlled by the splicing of non-coding 5exon(s), a mechanism conserved in humans. The S-MFN2 isoform has lower mitochondrial fusogenic capacity but seems critical for the trafficking and storage of neutral lipid. The genetically controlled tissue-specific ratio between L-MFN2 and S-MFN2 isoforms sheds important new light to understand both the tissue- and isoform-specificities of the MFN2 driven pathologies.

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DAVID, C., BARSA, C., EVAIN, C., KRÜGER, A., PAPIN, M., BERNADET, R., DURANTHON, G., MOLINIE, T., COUGOUILLES, E., DOMPIERRE, J., ROJO, M., LEFEVRE, A., PASDOIS, P., RORBACH, J., HABERMANN, B. H., MOURIER, A.. 2025-09-27. Non-coding exon splicing orchestrates tissue-specific expression of two functionally distinct mitochondrial isoforms of Mitofusin 2. https://doi.org/10.1101/2025.09.26.678759

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