Abstract

Age-related hearing loss (ARHL) is a highly prevalent sensory neurodegenerative disorder that involves various molecular mechanisms. The present study investigated if age-related oxidative stress (OS) induces alterations in mitochondrial DNA (mtDNA) copy number and heteroplasmy, using complementary in vivo and in vitro models. Aged (30-month) CBA/CaJ mice have elevated auditory brainstem response (ABR) thresholds amplitudes vs. young (3-month) CBA/CaJ mice, a key physiological characteristic of ARHL The in vitro experiments employed the strial SV-K1 cochlear cell line treated with hydrogen peroxide (H2O2). Both the aged cochleae and H2O2-treated cells exhibited a significant (∼50 %) reduction in mtDNA copy number compared to their respective controls with enhanced levels of malondialdehyde (MDA). Therefore, in both the in vivo and in vitro models, OS drove mtDNA depletion. High-depth sequencing employing nuclear mtDNA pseudogene (NUMT)-avoidant methodologies revealed non-random distribution of heteroplasmic variants. Mutation hotspots were identified within the mitochondrial genome, particularly in regions encoding cytochrome c oxidase subunit 1 (COX1) and cytochrome b (CYTB) in both models. While H2O2 treatment induced a more widespread expansion of low-frequency variants, aging mice primarily showed shifts in the allele frequency distribution of existing variants rather than an accumulation of novel mutations. These findings demonstrate that OS is also a key factor of mtDNA regional mutational burden in the aging cochlea. The parallel mtDNA alterations observed in aged tissues and OS cells underscore mitochondrial genomic instability as a central mechanism in ARHL, highlighting potential targets for interventions aimed at preserving mitochondrial integrity and therefore auditory function.

Department(s)

Chemical and Biochemical Engineering

Publication Status

Complimentary Access

Comments

Missouri University of Science and Technology, Grant NIH-NIA PO1 AG 009524

Keywords and Phrases

Age-related hearing loss; Aging; Cochlea; Gene; Mitochondrion; Mutation; Oxidative stress

International Standard Serial Number (ISSN)

1878-5891; 0378-5955

Document Type

Article - Journal

Document Version

Citation

File Type

text

Language(s)

English

Rights

© 2026 Elsevier, All rights reserved.

Publication Date

01 Jan 2026

PubMed ID

41308562

Download

Full Text Link

Share

 
COinS