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

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

doi:10.3389/fncel.2021.804345

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

Front Cell Neurosci. 2021 Dec 15:15:804345. doi: 10.3389/fncel.2021.804345. eCollection 2021.

Authors

Pengcheng Xu^{1

2

3}, Longhao Wang^{1

2

3}, Hu Peng⁴, Huihui Liu^{1

2

3}, Hongchao Liu^{1

2

3}, Qingyue Yuan^{1

2

3}, Yun Lin^{1

2

3}, Jun Xu^{1

2

3}, Xiuhong Pang⁵, Hao Wu^{1

2

3}, Tao Yang^{1

2

3}

Affiliations

¹ Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China.
⁴ Department of Otolaryngology-Head and Neck Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
⁵ Department of Otolaryngology-Head and Neck Surgery, Taizhou People's Hospital, The Fifth Affiliated Hospital of Nantong University, Taizhou, China.

Abstract

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.

Keywords: HARS2; apoptosis; hair cells; hearing loss; mitochondrial.