Hearing Impairment in a Mouse Model of Diabetes Is Associated with Mitochondrial Dysfunction, Synaptopathy, and Activation of the Intrinsic Apoptosis Pathway.

Ah-Ra Lyu,Yang Yu,Min Jung Park,Yong-Ho Park,Yang Hoon Huh,A Reum Je,Eung-Hyub Kim,Sun-Ae Shin,Tae-Hwan Kim,Akanksha Gajbhiye,Hyuk-Chan Kwon

doi:10.3390/ijms22168807

Abstract

Although previous studies continuously report an increased risk of hearing loss in diabetes patients, the impact of the disease on the inner ear remains unexplored. Herein, we examine the pathophysiology of diabetes-associated hearing impairment and cochlear synaptopathy in a mouse model of diabetes. Male B6.BKS(D)-Leprdb/J (db/db, diabetes) and heterozygote (db/+, control) mice were assigned into each experimental group (control vs. diabetes) based on the genotype and tested for hearing sensitivity every week from 6 weeks of age. Each cochlea was collected for histological and biological assays at 14 weeks of age. The diabetic mice exerted impaired hearing and a reduction in cochlear blood flow and C-terminal-binding protein 2 (CtBP2, a presynaptic ribbon marker) expression. Ultrastructural images revealed severely damaged mitochondria from diabetic cochlea accompanied by a reduction in Cytochrome c oxidase subunit 4 (COX4) and CR6-interacting factor 1 (CRIF1). The diabetic mice presented significantly decreased levels of platelet endothelial cell adhesion molecule (PECAM-1), B-cell lymphoma 2 (BCL-2), and procaspase-9, but not procaspase-8. Importantly, significant changes were not found in necroptotic programmed cell death markers (receptor-interacting serine/threonine-protein kinase 1, RIPK1; RIPK3; and mixed lineage kinase domain-like pseudokinase, MLKL) between the groups. Taken together, diabetic hearing loss is accompanied by synaptopathy, microangiopathy, damage to the mitochondrial structure/function, and activation of the intrinsic apoptosis pathway. Our results imply that mitochondrial dysfunction is deeply involved in diabetic hearing loss, and further suggests the potential benefits of therapeutic strategies targeting mitochondria.

Highlights

Sudden or gradual hearing loss has been reported in patients with diabetes [1]
Mitochondrial dysfunction, and synaptopathy are responsible for hearing impairment in the inner ear of hyperglycemic, insulin-resistant mice
Aged C57BL/6J mice (20 months old) showed marked increases in the expression of all three necroptotic markers, RIPK1, RIPK3, and mixedlineage kinase domain-like (MLKL), in the cochlea, suggesting an association between age-related hearing loss and the activation of necroptotic cell death signaling in the inner ear

Summary

Introduction

Sudden or gradual hearing loss has been reported in patients with diabetes [1]. According to studies in the USA and Japan, the incidence of hearing loss in patients with diabetes is double that in the general population [2,3]. The cell-surface protein, PECAM-1, is highly expressed on the surface of endothelial cells, in cell–cell junctions, and plays important roles in the maintenance of vascular integrity, cell adhesion, and signaling. Recent studies have indicated that PECAM-1/CD31 transmits survival signals into blood and vascular cells, where it functions as a potent inhibitor of mitochondria-dependent apoptosis [8,9]

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Results

Conclusion