Search Results (8)

Although cisplatin plays a vital role in chemotherapy protocols, its impact on hearing should not be overlooked. The ototoxic effects of cisplatin can lead to hearing loss. Childhood hearing loss can significantly impact various aspects of development. Understanding the mechanism of cisplatin-induced ototoxicity is crucial due to its high level of complexity. The process involves multiple interconnected steps, ranging from cisplatin absorption to its interaction with the cellular antioxidant defense system, nuclear DNA, mitochondria, and the cytokine cascade. Each of these interactions contributes to the overall pathophysiology of ototoxicity and is closely interrelated. Based on these, various hypotheses and conclusions were outlined, and we tried to analyze them as broadly as possible. Knowledge of these mechanisms has given rise to promising avenues and otoprotection strategies to combat ototoxicity. Although there is only one drug approved by the FDA (Food and Drug Administration), there are numerous drugs that target the mechanisms presented, but that need more evidence to be able to be used safely. In addition to these, the role of the multidisciplinary team should not be neglected and protocols should be established for periodic follow-up of patients treated with cisplatin to prevent hearing loss. This narrative review aims to point out all the aspects presented, based on the analysis of the literature and the conclusions drawn over time. We have selected the articles of interest and analyzed the studies that have obtained promising results to bring an overview of how cisplatin acts at the cochlear level, what can be done to combat these mechanisms, what solutions exist now and how we can prevent hearing loss. Full article

Background: Mitochondrial substrate switching plays an important role in aging. The substrate metabolic rate is closely related to mitochondrial activity, as mitochondria are the primary site for substrate oxidation and ATP production. Different substrates (glucose, amino acids, and fatty acids) enter the mitochondria through distinct pathways and are metabolized at different rates, depending on the energy demand and cellular conditions. However, it remains unclear how the mitochondrial metabolic rate of these substrates affects auditory cellular function. This study aimed to characterize the substrate-dependent mitochondrial respiratory responses of cochlear cells under varying energy supply conditions and metabolic stress, focusing on glucose, amino acids, and fatty acids as representative energy sources. Methods: The oxygen consumption rate (OCR) was measured after substrate addition using an Agilent Seahorse XF24 Flux Analyzer In-House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, and the maximum OCR (MOCR) was determined as part of the mitochondrial stress test. Statistical analyses were performed using analysis of variance (ANOVA). Results: The OCR increased significantly after glutamine (L-Gln) or palmitate addition. The MOCR after L-Gln addition was significantly higher than that after glutamic acid, glycine, and phenylalanine addition. The MOCR after pyruvate addition was significantly higher than that after glucose addition. However, there was no significant increase in the MOCR after fatty acid addition. Conclusions: Glucose is essential for basal metabolism but cannot rapidly meet sudden energy demands. Pyruvate and L-Gln serve as effective substrates for short-term, high-intensity energy demands. Fatty acids increase OCR through mitochondrial uncoupling effects, though their role may be limited in inner ear cells. These findings provide a foundation for exploring metabolic interventions to support cochlear function and hearing health. Full article

Hearing is essential for communication, and its loss can cause a serious disruption to one’s social life. Hearing loss is also recognized as a major risk factor for dementia; therefore, addressing hearing loss is a pressing global issue. Sensorineural hearing loss, the predominant type of hearing loss, is mainly due to damage to the inner ear along with a variety of pathologies including ischemia, noise, trauma, aging, and ototoxic drugs. In addition to genetic factors, oxidative stress has been identified as a common mechanism underlying several cochlear pathologies. The cochlea, which plays a major role in auditory function, requires high-energy metabolism and is, therefore, highly susceptible to oxidative stress, particularly in the mitochondria. Based on these pathological findings, the potential of antioxidants for the treatment of hearing loss has been demonstrated in several animal studies. However, results from human studies are insufficient, and future clinical trials are required. This review discusses the relationship between sensorineural hearing loss and reactive oxidative species (ROS), with particular emphasis on age-related hearing loss, noise-induced hearing loss, and ischemia–reperfusion injury. Based on these mechanisms, the current status and future perspectives of ROS-targeted therapy for sensorineural hearing loss are described. Full article

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. Full article

Although previous studies continuously report an increased risk of hearing loss in diabetes patients, the impact of the disease on the inner ear remains unexplored. Herein, we examine the pathophysiology of diabetes-associated hearing impairment and cochlear synaptopathy in a mouse model of diabetes. Male B6.BKS(D)-Lepr^db/J (db/db, diabetes) and heterozygote (db/+, control) mice were assigned into each experimental group (control vs. diabetes) based on the genotype and tested for hearing sensitivity every week from 6 weeks of age. Each cochlea was collected for histological and biological assays at 14 weeks of age. The diabetic mice exerted impaired hearing and a reduction in cochlear blood flow and C-terminal-binding protein 2 (CtBP2, a presynaptic ribbon marker) expression. Ultrastructural images revealed severely damaged mitochondria from diabetic cochlea accompanied by a reduction in Cytochrome c oxidase subunit 4 (COX4) and CR6-interacting factor 1 (CRIF1). The diabetic mice presented significantly decreased levels of platelet endothelial cell adhesion molecule (PECAM-1), B-cell lymphoma 2 (BCL-2), and procaspase-9, but not procaspase-8. Importantly, significant changes were not found in necroptotic programmed cell death markers (receptor-interacting serine/threonine-protein kinase 1, RIPK1; RIPK3; and mixed lineage kinase domain-like pseudokinase, MLKL) between the groups. Taken together, diabetic hearing loss is accompanied by synaptopathy, microangiopathy, damage to the mitochondrial structure/function, and activation of the intrinsic apoptosis pathway. Our results imply that mitochondrial dysfunction is deeply involved in diabetic hearing loss, and further suggests the potential benefits of therapeutic strategies targeting mitochondria. Full article

The relationship between type 1 diabetes and hearing loss is not well known, although based on many pathological studies, type 2 diabetes induced hearing loss is associated with microcirculation problems in the inner ear. The purpose of this study was to investigate the correlation between type 1 diabetes and hearing loss through hearing function and immunohistochemical analyses using type 1 diabetic Akita or wild-type (WT) mice. The Akita mice had a significant increase in hearing thresholds, blood glucose, and insulin tolerance compared to WT mice. Histological analysis showed that the loss of cells and damage to mitochondria in the spiral ganglion neurons of Akita mice were significantly increased compared to WT. Also, the stria vascularis showed decreased thickness, loss of intermediate cells, and disturbance in blood capillary shape in the Akita mice. Moreover, a reduction in type I, II, and IV fibrocytes and Na⁺/K⁺-ATPase α1 expression in spiral ligament was also observed. Cleaved caspase-3 expression was highly expressed in spiral ganglion neurons. In conclusion, hearing loss in type 1 diabetes is caused not only by ion imbalance and blood flow disorders of cochlear endolymph, but through the degenerative nervous system via apoptosis-mediated cell death. Full article

Age-related hearing loss (ARHL) is an irreversible, progressive neurodegenerative disorder and is presently untreatable. Previous studies using animal models have suggested mitochondrial damage and programmed cell death to be involved with ARHL. Thus, we further investigated the pathophysiologic role of mitochondria and necroptosis in aged C57BL/6J male mice. Aged mice (20 months old) exhibited a significant loss of hearing, number of hair cells, neuronal fibers, and synaptic ribbons compared to young mice. Ultrastructural analysis of aged cochleae revealed damaged mitochondria with absent or disorganized cristae. Aged mice also showed significant decrease in cochlear blood flow, and exhibited increase in gene expression of proinflammatory cytokines (IL-1β, IL-6, and TNF-α), receptor-interacting serine/threonine-protein kinase 1 and 3 (RIPK1 and RIPK3) and the pseudokinase mixed-lineage kinase domain-like (MLKL). Immunofluorescence (IF) assays of cytochrome C oxidase I (COX1) confirmed mitochondrial dysfunction in aged cochleae, which correlated with the degree of mitochondrial morphological damage. IF assays also revealed localization and increased expression of RIPK3 in sensorineural tissues that underwent significant necroptosis (inner and outer hair cells and stria vascularis). Together, our data shows that the aging cochlea exhibits damaged mitochondria, enhanced synthesis of proinflammatory cytokines, and provides new evidence of necroptosis in the aging cochlea in in vivo. Full article

Mitochondrial dysfunction is associated with the etiologies of sensorineural hearing loss, such as age-related hearing loss, noise- and ototoxic drug-induced hearing loss, as well as hearing loss due to mitochondrial gene mutation. Mitochondria are the main sources of reactive oxygen species (ROS) and ROS-induced oxidative stress is involved in cochlear damage. Moreover, the release of ROS causes further damage to mitochondrial components. Antioxidants are thought to counteract the deleterious effects of ROS and thus, may be effective for the treatment of oxidative stress-related diseases. The administration of mitochondria-targeted antioxidants is one of the drug delivery systems targeted to mitochondria. Mitochondria-targeted antioxidants are expected to help in the prevention and/or treatment of diseases associated with mitochondrial dysfunction. Of the various mitochondria-targeted antioxidants, the protective effects of MitoQ and SkQR1 against ototoxicity have been previously evaluated in animal models and/or mouse auditory cell lines. MitoQ protects against both gentamicin- and cisplatin-induced ototoxicity. SkQR1 also provides auditory protective effects against gentamicin-induced ototoxicity. On the other hand, decreasing effect of MitoQ on gentamicin-induced cell apoptosis in auditory cell lines has been controversial. No clinical studies have been reported for otoprotection using mitochondrial-targeted antioxidants. High-quality clinical trials are required to reveal the therapeutic effect of mitochondria-targeted antioxidants in terms of otoprotection in patients. Full article