Novel Role of the Mitochondrial Protein Fus1 in Protection from Premature Hearing Loss<i>via</i>Regulation of Oxidative Stress and Nutrient and Energy Sensing Pathways in the Inner Ear

Tan, Winston; Song, Lei; Graham, Morven; Schettino, Amy; Navaratnam, Dhasakumar; Yarbrough, Wendell G.; Santos‐Sacchi, Joseph; Ivanova, Alla V.

doi:10.1089/ars.2016.6851

Cited by 32 publications

(65 citation statements)

References 76 publications

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“…The analysis was performed off-line in BioSig (BioSig Technologies) on traces with visible peaks by setting cursors at the maxima and minima of the peaks. Latency was defined as the time from the onset of the stimulus to the peak, while amplitude was measured by taking the mean of the ⌬V of the positive and negative deflections of the ABR wave (Tan et al, 2017).…”

Section: Methodsmentioning

confidence: 99%

Modulators of Kv3 Potassium Channels Rescue the Auditory Function of Fragile X Mice

El-Hassar

Song

Tan³

et al. 2019

J. Neurosci.

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Fragile X syndrome (FXS) is characterized by hypersensitivity to sensory stimuli, including environmental sounds. We compared the auditory brainstem response (ABR) recorded in vivo in mice lacking the gene (Fmr1 ؊/y ) for fragile X mental retardation protein (FMRP) with that in wild-type animals. We found that ABR wave I, which represents input from the auditory nerve, is reduced in Fmr1 ؊/y animals, but only at high sound levels. In contrast, wave IV, which represents the activity of auditory brainstem nuclei is enhanced at all sound levels, suggesting that loss of FMRP alters the central processing of auditory signals. Current-clamp recordings of neurons in the medial nucleus of the trapezoid body in the auditory brainstem revealed that, in contrast to neurons from wild-type animals, sustained depolarization triggers repetitive firing rather than a single action potential. In voltage-clamp recordings, K ϩ currents that activate at positive potentials ("high-threshold" K ϩ currents), which are required for high-frequency firing and are carried primarily by Kv3.1 channels, are elevated in Fmr1 ؊/y mice, while K ϩ currents that activate near the resting potential and inhibit repetitive firing are reduced. We therefore tested the effects of AUT2 [((4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-(1-methylethyl) benzonitrile], a compound that modulates Kv3.1 channels. AUT2 reduced the high-threshold K ϩ current and increased the low-threshold K ϩ currents in neurons from Fmr1 ؊/y animals by shifting the activation of the high-threshold current to more negative potentials. This reduced the firing rate and, in vivo, restored wave IV of the ABR. Our results from animals of both sexes suggest that the modulation of the Kv3.1 channel may have potential for the treatment of sensory hypersensitivity in patients with FXS. Key words: auditory brainstem response; AUT2; fragile X; high-and low-threshold potassium channels; medial nucleus of the trapezoid body; potassium channelsSignificance Statement mRNA encoding the Kv3.1 potassium channel was one of the first described targets of the fragile X mental retardation protein (FMRP). Fragile X syndrome is caused by loss of FMRP and, in humans and mice, causes hypersensitivity to auditory stimuli. We found that components of the auditory brain response (ABR) corresponding to auditory brainstem activity are enhanced in mice lacking FMRP. This is accompanied by hyperexcitability and altered potassium currents in auditory brainstem neurons. Treatment with a drug that alters the voltage dependence of Kv3.1 channels normalizes the imbalance of potassium currents, as well as ABR responses in vivo, suggesting that such compounds may be effective in treating some symptoms of fragile X syndrome.

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Section: Methodsmentioning

confidence: 99%

Modulators of Kv3 Potassium Channels Rescue the Auditory Function of Fragile X Mice

El-Hassar

Song

Tan³

et al. 2019

J. Neurosci.

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“…Besides the data presented in this manuscript that we discuss below, we recently showed that Fus1 KO mice prematurely and progressively lose their hearing [63]. Early deterioration of hearing parameters measured in young adult Fus1 KO mice via Auditory Brainstem Response (ABR) and molecular perturbations in their cochleae were similar to the aging-related processes that occur in people of 70 years of age and older.…”

Section: Discussionmentioning

confidence: 76%

Mitochondrial protein Fus1/Tusc2 in premature aging and age-related pathologies: critical roles of calcium and energy homeostasis

Uzhachenko

Boyd

Olivares–Villagómez

et al. 2017

Aging

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Decreased energy production and increased oxidative stress are considered to be major contributors to aging and aging-associated pathologies. The role of mitochondrial calcium homeostasis has also been highlighted as an important factor affecting different pathological conditions. Here, we present evidence that loss of a small mitochondrial protein Fus1 that maintains mitochondrial homeostasis results in premature aging, aging-associated pathologies, and decreased survival. We showed that Fus1KO mice develop multiple early aging signs including lordokyphosis, lack of vigor, inability to accumulate fat, reduced ability to tolerate stress, and premature death. Other prominent pathological changes included low sperm counts, compromised ability of adult stem cells to repopulate tissues, and chronic inflammation. At the molecular level, we demonstrated that mitochondria of Fus1 KO cells have low reserve respiratory capacity (the ability to produce extra energy during sudden energy demanding situations), and show significantly altered dynamics of cellular calcium response.Our recent studies on early hearing and memory loss in Fus1 KO mice combined with the new data presented here suggest that calcium and energy homeostasis controlled by Fus1 may be at the core of its aging-regulating activities. Thus, Fus1 protein and Fus1-dependent pathways and processes may represent new tools and targets for anti-aging strategies.

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“…ABR experiments in this study were conducted using the same apparatus (TDT3 system with a FF1 speaker, Tucker-Davis Technologies) and procedures described in (Tan et al, 2017, El-Hassar et al, 2019. Auditory thresholds were determined based on waves I and II (see also Figure 5A).…”

Section: Auditory Brainstem Response (Abr)mentioning

confidence: 99%

Efferent feedback enforces bilateral coupling of spontaneous activity in the developing auditory system

Wang

Sanghvi

Gribizis

et al. 2020

Preprint

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SummaryIn the developing auditory system, spontaneous activity generated in the cochleae propagates into the central nervous system to promote circuit formation before hearing onset. Effects of the evolving peripheral firing pattern on spontaneous activity in the central auditory system are not well understood. Here, we describe the wide-spread bilateral coupling of spontaneous activity that coincides with the period of transient efferent modulation of inner hair cells from the medial olivochlear (MOC) system. Knocking out the α9/α10 nicotinic acetylcholine receptor, a requisite part of the efferent cholinergic pathway, abolishes these bilateral correlations. Pharmacological and chemogenetic experiments confirm that the MOC system is necessary and sufficient to produce the bilateral coupling. Moreover, auditory sensitivity at hearing onset is reduced in the absence of pre-hearing efferent modulation. Together, our results demonstrate how ascending and descending pathways collectively shape spontaneous activity patterns in the auditory system and reveal the essential role of the MOC efferent system in linking otherwise independent streams of bilateral spontaneous activity during the prehearing period.

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Novel Role of the Mitochondrial Protein Fus1 in Protection from Premature Hearing LossviaRegulation of Oxidative Stress and Nutrient and Energy Sensing Pathways in the Inner Ear

Cited by 32 publications

References 76 publications

Modulators of Kv3 Potassium Channels Rescue the Auditory Function of Fragile X Mice

Modulators of Kv3 Potassium Channels Rescue the Auditory Function of Fragile X Mice

Mitochondrial protein Fus1/Tusc2 in premature aging and age-related pathologies: critical roles of calcium and energy homeostasis

Efferent feedback enforces bilateral coupling of spontaneous activity in the developing auditory system

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