GPRASP2 deficiency contributes to apoptosis in the spiral ganglion cells via the AMPK/DRP1 signaling pathway
Kun Huang,
Jing Cai,
Yajie Lu,
Tianming Wang,
Shen Yue,
Qinjun Wei,
Jun Yao,
Zhibin Chen,
Xin Cao
Affiliations
Kun Huang
Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, Nanjing, China
Jing Cai
Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, Nanjing, China
Yajie Lu
Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China
Tianming Wang
Central Laboratory, Translational Medicine Research Center, the Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
Shen Yue
Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, Nanjing, China
Qinjun Wei
Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China
Jun Yao
Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China; Corresponding author. Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, No.101 Longmian Avenue, Nanjing, 211166, China.
Zhibin Chen
Department of Otolaryngology, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China; Corresponding author. Department of Otolaryngology, the First Affiliated Hospital with Nanjing Medical University, No.300 Guangzhou Road, Nanjing, 210029, China.
Xin Cao
Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China; Corresponding author. Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, No.101 Longmian Avenue, Nanjing, 211166, China.
G protein-coupled receptor-associated sorting protein 2 (GPRASP2) deficiency has been implicated in immunological inflammation, cancers, and neurological disorders. Our previous work revealed that the pathogenic mutation in GPRASP2 was responsible for X-linked recessive syndromic hearing loss (SHL). Given the specific high expression of GPRASP2 in the spiral ganglion, GPRASP2 likely contributes to the maintenance and functionality of neurons, potentially playing a role in synaptic transmission. The impact of GPRASP2 deficiency on spiral ganglion cells (SGCs) and their underlying pathogenic mechanisms will be investigated in this study. The primary culture of SGCs obtained from mouse cochleae was treated with Gprasp2-targeting short hairpin RNA (Gprasp2-shRNA) via lentivirus infection. The results showed that GPRASP2 deficiency enhanced SGCs apoptosis and decreased cell viability. Meanwhile, a significant abnormality of mitochondrial morphology and decreased membrane potential were observed in GPRASP2-deficient SGCs. These effects could be mitigated by treatment with the mitochondrial division inhibitor 1 (Mdivi-1). In addition to enhancing SGCs apoptosis and decreasing cell viability, GPRASP2 deficiency also inhibited the development of SGCs in mouse cochlear explant culture. Our study further revealed that this deficiency resulted in increased phosphorylation of AMPK and activation of the AMPK/DRP1 pathway, promoting SGCs apoptosis. These findings provide insight into the pathogenic mechanisms by which GPRASP2 deficiency is implicated in auditory dysfunction.
