title: Novel Role of the Mitochondrial Protein Fus1 in Protection from Premature Hearing Loss via Regulation of Oxidative Stress and Nutrient and Energy Sensing Pathways in the Inner Ear.
abstract: Acquired hearing loss is a worldwide epidemic that affects all ages. It is multifactorial in etiology with poorly characterized molecular mechanisms. Mitochondria are critical components in hearing. Here, we aimed to identify the mechanisms of mitochondria-dependent hearing loss using Fus1 KO mice, our novel model of mitochondrial dysfunction/oxidative stress.
  
  
  
  Using auditory brainstem responses (ABRs), we characterized the Fus1 KO mouse as a novel, clinically relevant model of age-related hearing loss (ARHL) of metabolic etiology. We demonstrated early decline of the endocochlear potential (EP) that may occur due to severe mitochondrial and vascular pathologies in the Fus1 KO cochlear stria vascularis. We showed that pathological alterations in antioxidant (AO) and nutrient and energy sensing pathways (mTOR and PTEN/AKT) occur in cochleae of young Fus1 KO mice before major hearing loss. Importantly, short-term AO treatment corrected pathological molecular changes, while longer AO treatment restored EP, improved ABR parameters, restored mitochondrial structure, and delayed the development of hearing loss in the aging mouse.
  
  
  
  Currently, no molecular mechanisms linked to metabolic ARHL have been identified. We established pathological and molecular mechanisms that link the disease to mitochondrial dysfunction and oxidative stress.
  
  
  
  Since chronic mitochondrial dysfunction is common in many patients, it could lead to developing hearing loss that can be alleviated/rescued by AO treatment. Our study creates a framework for clinical trials and introduces the Fus1 KO model as a powerful platform for developing novel therapeutic strategies to prevent/delay hearing loss associated with mitochondrial dysfunction. Antioxid. Redox Signal. 27, 489-509.
authors.affiliation: 1 Department of Surgery, Section of Otolaryngology, Yale University School of Medicine , New Haven, Connecticut.
authors.forename: Winston J T
authors.initials: WJT
authors.lastname: Tan
authors.affiliation: 2 Department of Otolaryngology-Head and Neck Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai, China .|3 Ear Institute, Shanghai Jiao Tong University School of Medicine , Shanghai, China .|4 Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases , Shanghai, China .
authors.forename: Lei
authors.initials: L
authors.lastname: Song
authors.affiliation: 5 CCMI EM Core Facility, Yale University School of Medicine , New Haven, Connecticut.
authors.forename: Morven
authors.initials: M
authors.lastname: Graham
authors.affiliation: 6 Yale School of Medicine , New Haven, Connecticut.
authors.forename: Amy
authors.initials: A
authors.lastname: Schettino
authors.affiliation: 7 Department of Neurology, Yale University School of Medicine , New Haven, Connecticut.|8 Department of Neuroscience, Yale University School of Medicine , New Haven, Connecticut.
authors.forename: Dhasakumar
authors.initials: D
authors.lastname: Navaratnam
authors.affiliation: 1 Department of Surgery, Section of Otolaryngology, Yale University School of Medicine , New Haven, Connecticut.|9 Department of Pathology, Yale University School of Medicine , New Haven, Connecticut.
authors.forename: Wendell G
authors.initials: WG
authors.lastname: Yarbrough
authors.affiliation: 1 Department of Surgery, Section of Otolaryngology, Yale University School of Medicine , New Haven, Connecticut.|8 Department of Neuroscience, Yale University School of Medicine , New Haven, Connecticut.|10 Department of Cellular and Molecular Physiology, Yale University School of Medicine , New Haven, Connecticut.
authors.forename: Joseph
authors.initials: J
authors.lastname: Santos-Sacchi
authors.affiliation: 1 Department of Surgery, Section of Otolaryngology, Yale University School of Medicine , New Haven, Connecticut.
authors.forename: Alla V
authors.initials: AV
authors.lastname: Ivanova
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D007758:Ear, Inner / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D055786:Gene Knockout Techniques; D034381:Hearing Loss / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013136:Spiral Ganglion / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D025521:Tumor Suppressor Proteins; C543627:Tusc2 protein, mouse; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; D000111:Acetylcysteine
keywords: Fus1/Tusc2; age-related hearing loss; antioxidants; mitochondria; spiral ganglion neurons; stria vascularis