Disruption of Hars2 in Cochlear Hair Cells Causes Progressive Mitochondrial Dysfunction and Hearing Loss in Mice

Pengcheng Xu; Pengcheng Xu; Pengcheng Xu; Longhao Wang; Longhao Wang; Longhao Wang; Hu Peng; Huihui Liu; Huihui Liu; Huihui Liu; Hongchao Liu; Hongchao Liu; Hongchao Liu; Qingyue Yuan; Qingyue Yuan; Qingyue Yuan; Yun Lin; Yun Lin; Yun Lin; Jun Xu; Jun Xu; Jun Xu; Xiuhong Pang; Hao Wu; Hao Wu; Hao Wu; Tao Yang; Tao Yang; Tao Yang

doi:10.3389/fncel.2021.804345

Frontiers in Cellular Neuroscience (Dec 2021)

Disruption of Hars2 in Cochlear Hair Cells Causes Progressive Mitochondrial Dysfunction and Hearing Loss in Mice

Pengcheng Xu,
Pengcheng Xu,
Pengcheng Xu,
Longhao Wang,
Longhao Wang,
Longhao Wang,
Hu Peng,
Huihui Liu,
Huihui Liu,
Huihui Liu,
Hongchao Liu,
Hongchao Liu,
Hongchao Liu,
Qingyue Yuan,
Qingyue Yuan,
Qingyue Yuan,
Yun Lin,
Yun Lin,
Yun Lin,
Jun Xu,
Jun Xu,
Jun Xu,
Xiuhong Pang,
Hao Wu,
Hao Wu,
Hao Wu,
Tao Yang,
Tao Yang,
Tao Yang

Affiliations

Pengcheng Xu: Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Pengcheng Xu: Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Pengcheng Xu: Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China
Longhao Wang: Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Longhao Wang: Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Longhao Wang: Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China
Hu Peng: Department of Otolaryngology-Head and Neck Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
Huihui Liu: Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Huihui Liu: Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Huihui Liu: Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China
Hongchao Liu: Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Hongchao Liu: Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Hongchao Liu: Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China
Qingyue Yuan: Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Qingyue Yuan: Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Qingyue Yuan: Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China
Yun Lin: Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yun Lin: Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yun Lin: Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China
Jun Xu: Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Jun Xu: Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Jun Xu: Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China
Xiuhong Pang: Department of Otolaryngology-Head and Neck Surgery, Taizhou People’s Hospital, The Fifth Affiliated Hospital of Nantong University, Taizhou, China
Hao Wu: Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Hao Wu: Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Hao Wu: Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China
Tao Yang: Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Tao Yang: Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Tao Yang: Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China

DOI: https://doi.org/10.3389/fncel.2021.804345
Journal volume & issue: Vol. 15

Abstract

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Mutations in a number of genes encoding mitochondrial aminoacyl-tRNA synthetases lead to non-syndromic and/or syndromic sensorineural hearing loss in humans, while their cellular and physiological pathology in cochlea has rarely been investigated in vivo. In this study, we showed that histidyl-tRNA synthetase HARS2, whose deficiency is associated with Perrault syndrome 2 (PRLTS2), is robustly expressed in postnatal mouse cochlea including the outer and inner hair cells. Targeted knockout of Hars2 in mouse hair cells resulted in delayed onset (P30), rapidly progressive hearing loss similar to the PRLTS2 hearing phenotype. Significant hair cell loss was observed starting from P45 following elevated reactive oxygen species (ROS) level and activated mitochondrial apoptotic pathway. Despite of normal ribbon synapse formation, whole-cell patch clamp of the inner hair cells revealed reduced calcium influx and compromised sustained synaptic exocytosis prior to the hair cell loss at P30, consistent with the decreased supra-threshold wave I amplitudes of the auditory brainstem response. Starting from P14, increasing proportion of morphologically abnormal mitochondria was observed by transmission electron microscope, exhibiting swelling, deformation, loss of cristae and emergence of large intrinsic vacuoles that are associated with mitochondrial dysfunction. Though the mitochondrial abnormalities are more prominent in inner hair cells, it is the outer hair cells suffering more severe cell loss. Taken together, our results suggest that conditional knockout of Hars2 in mouse cochlear hair cells leads to accumulating mitochondrial dysfunction and ROS stress, triggers progressive hearing loss highlighted by hair cell synaptopathy and apoptosis, and is differentially perceived by inner and outer hair cells.

Published in Frontiers in Cellular Neuroscience

ISSN: 1662-5102 (Online)
Publisher: Frontiers Media S.A.
Country of publisher: Switzerland
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: http://www.frontiersin.org/cellular-neuroscience

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