Pharmacological Modulation of Energy and Metabolic Pathways Protects Hearing in the Fus1/Tusc2 Knockout Model of Mitochondrial Dysfunction and Oxidative Stress

• Published in: Antioxidants 2023-06, Vol.12 (6), p.1225
• Main Authors: Tan, Winston J T, Santos-Sacchi, Joseph, Tonello, Jane, Shanker, Anil, Ivanova, Alla V
• Format: Article
• Language: English
• Subjects: age-related hearing loss; Aging; Analysis; Apoptosis; Autophagy; Bioenergetics; Calcium channels (voltage-gated); Channel gating; Cochlea; Cytoskeleton; Drinking water; Ear diseases; Ears & hearing; Energy; Fus1/Tusc2; Gene expression; Genes; Glucose; Glycolysis; Hearing loss; Hearing protection; Hypothalamus; Immune response; Immunosuppressive agents; Instrument industry; Laboratory animals; Metabolic pathways; Metabolism; Mice; Mitochondria; Mitochondrial DNA; mitochondrial dysfunction; Oxidation; Oxidative stress; Pituitary; Protein transport; Proteins; Rapamycin; TOR protein
• ISSN: 2076-3921; 2076-3921
• DOI: 10.3390/antiox12061225

Tightly regulated and robust mitochondrial activities are critical for normal hearing. Previously, we demonstrated that Fus1/Tusc2 KO mice with mitochondrial dysfunction exhibit premature hearing loss. Molecular analysis of the cochlea revealed hyperactivation of the mTOR pathway, oxidative stress, and altered mitochondrial morphology and quantity, suggesting compromised energy sensing and production. Here, we investigated whether the pharmacological modulation of metabolic pathways using rapamycin (RAPA) or 2-deoxy-D-glucose (2-DG) supplementation can protect against hearing loss in female Fus1 KO mice. Additionally, we aimed to identify mitochondria- and Fus1/Tusc2-dependent molecular pathways and processes critical for hearing. We found that inhibiting mTOR or activating alternative mitochondrial energetic pathways to glycolysis protected hearing in the mice. Comparative gene expression analysis revealed the dysregulation of critical biological processes in the KO cochlea, including mitochondrial metabolism, neural and immune responses, and the cochlear hypothalamic-pituitary-adrenal axis signaling system. RAPA and 2-DG mostly normalized these processes, although some genes showed a drug-specific response or no response at all. Interestingly, both drugs resulted in a pronounced upregulation of critical hearing-related genes not altered in the non-treated KO cochlea, including cytoskeletal and motor proteins and calcium-linked transporters and voltage-gated channels. These findings suggest that the pharmacological modulation of mitochondrial metabolism and bioenergetics may restore and activate processes critical for hearing, thereby protecting against hearing loss.