These data have led to the recognition of an unrecognized role of AIF variants in the occurrence of ANSD via their regulatory effects on mitochondrial functions. Hearing loss has been identified among the symptoms of some known mitochondrial diseases, indicating that mitochondrial functions are crucial to auditory pathways. AIF knockdown in SGNs impaired mitochondrial respiration and disrupted membrane potential, indicating the vital role of AIF in mitochondrial functions. The dimeric form enables essential mitochondrial functions by binding to CHCHD4. AIF is present in a state of monomer-dimer equilibrium in mitochondria. ![]() AIF undergoes dimerization and conformational changes to form an air-stable FADH It plays dual roles in cell death and survival. The SGNs and auditory nerves were identified as lesion sites.Īpoptosis-inducing factor (AIF), encoded by AIFM1, is a flavoprotein located in the inner mitochondrial membrane space. The patients presented with childhood-onset auditory neuropathy and delayed peripheral sensory neuropathy, with other symptoms including tinnitus, unsteadiness, and numbness in the extremities. We previously identified an ANSD pedigree with an AIFM1 c.1265 G > A variant. Previous studies have identified several pathogenic genes for ANSD however, their mechanisms have remained poorly understood. Auditory neuropathy spectrum disorder is a major public health concern that places a substantial burden on families and society. Approximately 1/7000 newborns have abnormal auditory nerve function, which accounts for 10%-14% of cases of permanent hearing loss in children. Our findings help elucidate the mechanism of ANSD and may lead to the provision of novel therapies.Īuditory neuropathy spectrum disorder (ANSD) is a type of hearing impairment caused by the dysfunction of inner hair cells (IHCs), ribbon synapses, spiral ganglion neurons (SGNs) and/or the auditory nerve itself. Mitochondrial dysfunction, especially mCa 2+ overload, plays a prominent role in ANSD associated with AIFM1. ![]() This study demonstrates that the AIFM1 variant is one of the molecular bases of ANSD. Interestingly, correction of the AIFM1 variant significantly restored the structure and function of AIF, further improving the physiological state of patient-specific iPSC-derived neurons. Calpain was activated by mCa 2+ and subsequently cleaved AIF for its translocation into the nucleus, ultimately resulting in caspase-independent apoptosis. On the other hand, MICU1-MICU2 heterodimerization was impaired, leading to mCa 2+ overload. On the one hand, the mitochondrial import of ETC complex subunits was inhibited, subsequently leading to an increased ADP/ATP ratio and elevated ROS levels. Such impaired AIF dimerization then weakened the interaction between AIF and coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4). In patient cells (PBMCs, iPSCs, and neurons), the AIFM1 c.1265 G > A variant caused a novel splicing variant (c.1267-1305del), resulting in AIF p.R422Q and p.423-435del proteins, which impaired AIF dimerization. ![]() The pathogenic mechanism was explored in these neurons. These iPSCs were further differentiated into neurons via neural stem cells (NSCs). The patient-specific iPSCs were edited via CRISPR/Cas9 technology to generate gene-corrected isogenic iPSCs. We generated induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells (PBMCs) via nucleofection with episomal plasmids. Although we previously identified the AIFM1 c.1265 G > A variant to be associated with ANSD, the mechanism by which ANSD is associated with AIFM1 is poorly understood. Approximately 1/7000 newborns have abnormal auditory nerve function, accounting for 10%-14% of cases of permanent hearing loss in children. Auditory neuropathy spectrum disorder (ANSD) is a hearing impairment caused by dysfunction of inner hair cells, ribbon synapses, spiral ganglion neurons and/or the auditory nerve itself.
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