RT Journal Article
SR Electronic
T1 The MFN2 Q367H variant reveals a novel pathomechanism connected to mtDNA-mediated inflammation
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202402921
DO 10.26508/lsa.202402921
VO 8
IS 6
A1 Zaman, Mashiat
A1 Sharma, Govinda
A1 Almutawa, Walaa
A1 Soule, Tyler GB
A1 Sabouny, Rasha
A1 Joel, Matt
A1 Mohan, Armaan
A1 Chute, Cole
A1 Joseph, Jeffrey T
A1 Pfeffer, Gerald
A1 Shutt, Timothy E
YR 2025
UL http://www.life-science-alliance.org/content/8/6/e202402921.abstract
AB Pathogenic variants in the mitochondrial protein MFN2 are typically associated with a peripheral neuropathy phenotype, but can also cause a variety of additional pathologies including myopathy. Here, we identified an uncharacterized MFN2 variant, Q367H, in a patient diagnosed with late-onset distal myopathy, but without peripheral neuropathy. Supporting the hypothesis that this variant contributes to the patient’s 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 colocalized with early endosomes, and measured activation of both TLR9 and cGAS-STING inflammation pathways that sense mtDNA. Re-expressing the Q367H variant in MFN2 KO cells also induced mtDNA release, demonstrating this phenotype is a direct result of the variant. As elevated inflammation can cause myopathy, our findings linking the Q367H MFN2 variant with elevated TLR9 and cGAS-STING signalling can explain the patient’s 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 pathomechanism connecting MFN2 dysfunction to mtDNA-mediated inflammation.