Patient-specific variants of NFU1/NFU-1 cause aberrant cholinergic signaling in a Caenorhabditis elegans model of MMDS1.

Neuromuscular dysfunction is a common feature of mitochondrial diseases and frequently presents as ataxia, spasticity, and/or dystonia all of which can severely impact individuals afflicted with mitochondrial diseases. Dystonia is one of the most common symptoms of Multiple Mitochondrial Dysfunctions Syndrome 1, a disease associated with mutations in the causative gene (NFU1) that impairs iron-sulfur cluster biogenesis. We have generated C. elegans strains that recreated patient-specific point variants in the C. elegans ortholog (NFU-1) that result in allele-specific dysfunction. Each of these mutants, Gly147Arg and Gly166Cys, have altered acetylcholine signaling at neuromuscular junctions, but opposite effects on activity and motility. We find that the Gly147Arg variant is hypersensitive to acetylcholine and that knockdown of acetylcholine release rescues nearly all neuromuscular phenotypes of this variant. In contrast, we find that the Gly166Cys variant causes predominantly postsynaptic acetylcholine hypersensitivity due to an unclear mechanism. These results are important for understanding the neuromuscular conditions of MMDS1 patients and potential avenues for therapeutic intervention.