The MFN2 Q367H variant reveals a novel pathomechanism connected to mtDNA-mediated inflammation

Pathogenic variants in the mitochondrial protein MFN2 are typically associated with a peripheral neuropathy phenotype, but can also include a variety of additional pathologies including myopathy. Here, we identified a previously uncharacterized MFN2 variant, Q367H, in a patient diagnosed with late-onset distal myopathy, but without peripheral neuropathy. Consistent with the hypothesis that the Q367H MFN2 variant contributes to the patients pathology, patient fibroblasts and transdifferentiated myoblasts showed changes consistent with impairment of several MFN2 functions. We also observed mtDNA outside of the mitochondrial network that co-localized with early-endosomes, and measured activation of both TLR9 and cGAS-STING inflammation pathways that sense mtDNA. Notably, the inflammatory signaling was increased 3-10 fold in transdifferentiated patient myoblasts. We also found that re-expressing the Q367H variant in MFN2 knockout cells also induces mtDNA release. As elevated inflammation can cause myopathy, our findings linking the Q367H MFN2 variant with elevated TLR9 and cGAS-STING signaling that is exacerbated in myoblasts, can explain patients myopathy. Thus, we characterize a novel MFN2 variant in a patient with an atypical presentation that separates peripheral neuropathy and myopathy phenotypes, and establish a potential novel pathomechanism connecting MFN2 dysfunction to mtDNA-mediated inflammation.