ArticleCell death & disease2023
Impaired AIF-CHCHD4 interaction and mitochondrial calcium overload contribute to auditory neuropathy spectrum disorder in patient-iPSC-derived neurons with AIFM1 variant.
Article in Cell death & disease, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 15 citations in OpenAlex.
- Effects of electrical stimulation rate in genetically confirmed pre- and post-Synaptic auditory neuropathy in children.European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery · 2026Trial
- Mitochondrial regulation of brain development: evidence from zebrafish models.Fish physiology and biochemistry · 2026Review
- Metal-dependent regulated cell death: Molecular architecture and translational frontiers.iMeta · 2026Review
- A novel MMP13 frameshift variant causes short stature via enhanced MMP13-HSPA5 interaction and activated endoplasmic reticulum stress.Clinical and translational medicine · 2026Article
- Mitophagy Activation by N-Acetylcysteine Protects against Mic60 Deficiency-Induced Auditory Neuropathy.Neuroscience bulletin · 2026Article
- The Potential Role of Auditory Nerve Development in Sensorineural Hearing Loss: from Pathophysiology to Treatment Insights.International journal of medical sciences · 2026Review
- Calpain2-mediated downregulation of apoptosis-inducing factors impairs mitochondrial function in noise-induced spiral ganglion neuron degeneration.IBRO neuroscience reports · 2025Article
- Distinct genetic patterns and natural history of OPA1-related auditory neuropathy in Chinese population.Orphanet journal of rare diseases · 2025Article
- Nerve growth factor-loaded biomimetic prussian blue nanocomplexes for reversing osteoporosis via promoting osteoblast precursor cell proliferation and differentiation.Materials today. Bio · 2025Article
- CHCHD4 Oxidoreductase Activity: A Comprehensive Analysis of the Molecular, Functional, and Structural Properties of Its Redox-Regulated Substrates.Molecules (Basel, Switzerland) · 2025Review
- Timing and Graded BMP Signalling Determines Fate of Neural Crest and Ectodermal Placode Derivatives from Pluripotent Stem Cells.Biomedicines · 2024Review
- AIF translocation into nucleus caused by Aifm1 R450Q mutation: generation and characterization of a mouse model for AUNX1.Human molecular genetics · 2024Article
- Auditory Function and Natural History of 645 Auditory Neuropathy Patients Over a 27-Year Span in China.Ear and hearingArticle
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Authors and funding
20 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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. Approximately 1/7000 newborns have abnormal auditory nerve function, accounting for 10%-14% of cases of permanent hearing loss in children. 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. We generated induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells (PBMCs) via nucleofection with episomal plasmids. The patient-specific iPSCs were edited via CRISPR/Cas9 technology to generate gene-corrected isogenic iPSCs. These iPSCs were further differentiated into neurons via neural stem cells (NSCs). The pathogenic mechanism was explored in these neurons. 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. Such impaired AIF dimerization then weakened the interaction between AIF and coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4). 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. On the other hand, MICU1-MICU2 heterodimerization was impaired, leading to
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