Pathogenic Mitofusin 2 variants causing myopathy drive endosomal mtDNA release and inflammation

Abstract

Pathogenic variants in Mitofusin 2 (MFN2) cause the peripheral neuropathy Charcot-Marie-Tooth Type IIA (CMT2A), with a subset of patients presenting with myopathy. Yet how MFN2 dysfunction causes these phenotypes remains mechanistically undefined. Here, we identify a conserved pathomechanism in MFN2-linked myopathy variants, where mitochondrial DNA is released into RAB5 early endosomes, robustly activating TLR9 and cGAS-STING inflammatory signaling. We further show that MFN2 dysfunction drives two mechanistically distinct pools of extra-mitochondrial mtDNA, one in endosomes and the other present mitochondrial-derived vesicles (MDVs). These two pools of released mtDNA can be distinguished based on their size, with endosomal mtDNA forming larger puncta than mtDNA present in MDVs. Finally, we show that pharmacological activation of the integrated stress response reduces both pools of extra-mitochondrial mtDNA. Together, our work defines a conserved cellular phenotype linking MFN2 dysfunction to myopathy and suggests a tractable therapeutic strategy for mtDNA release-associated pathologies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/26363493v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@11ed166org.highwire.dtl.DTLVardef@45aa2corg.highwire.dtl.DTLVardef@1a734fforg.highwire.dtl.DTLVardef@886ad0_HPS_FORMAT_FIGEXP M_FIG C_FIG