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ORIGINAL RESEARCH article
Front. Cell. Neurosci.
Sec. Cellular Neurophysiology
Volume 19 - 2025 | doi: 10.3389/fncel.2025.1541347
Mitochonic acid 5 mitigates age-related hearing loss progression by targeting defective 2-methylthiolation in mitochondrial transfer RNAs
Provisionally accepted- 1 Osaka Metropolitan University, Osaka, Japan
- 2 Teikyo University Mizonokuchi Hospital, Kawasaki, Tokyo, Japan
- 3 Kyoto University, Kyoto, Kyōto, Japan
- 4 Tohoku University, Sendai, Miyagi, Japan
- 5 Kumamoto University, Kumamoto, Kumamoto, Japan
Introduction: Age-related hearing loss (ARHL) is linked to dementia, with mitochondrial dysfunction playing a key role in its progression. Deficient mitochondrial tRNA modifications impair protein synthesis and energy metabolism, accelerating ARHL. Mitochonic acid 5 (MA-5) has shown promise as a therapeutic candidate by improving mitochondrial function, reducing oxidative stress, and stabilizing membrane potential. Methods: In this study, we investigated the effects of MA-5 on ARHL in cyclin-dependent kinase 5 regulatory subunit-associated protein 1 (Cdk5rap1) knockout (KO) mice, which exhibit early-onset ARHL due to abnormalities in mitochondrial transfer RNA (mt-tRNA) modifications. Results: MA-5 treatment effectively attenuated ARHL progression in Cdk5rap1-KO mice by improving auditory brainstem response thresholds and distortion product otoacoustic emissions. It also reduced spiral ganglion and outer hair cell loss, while preserving the cochlear structural integrity by preventing mitochondrial degeneration in spiral ligament fibrocytes. Mechanistically, MA-5 upregulated the expression of silent information regulator sirtuin 1 and promoted the nuclear translocation of yes-associated protein, both of which are involved in regulating mitochondrial function and cellular senescence. Metabolomics analysis further demonstrated that MA-5 restored mitochondrial metabolism, reduced lactate accumulation, and maintained mitochondrial integrity. Conclusion: These findings suggest that MA-5 is a viable treatment option for ARHL and other age-related disorders associated with mitochondrial dysfunction.
Keywords: age-related hearing loss, mitochonic acid 5, Mitochondrial dysfunction, cyclindependent kinase 5 regulatory subunit-associated protein 1, 2-methylthiolation
Received: 07 Dec 2024; Accepted: 25 Mar 2025.
Copyright: © 2025 Kouga, Miwa, Wei, Sunami and Tomizawa. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Toru Miwa, Teikyo University Mizonokuchi Hospital, Kawasaki, 173-8606, Tokyo, Japan
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