Abstract
Age-dependent decrease of mitochondrial energy production and cellular redox imbalance play significant roles in age-related hearing loss (ARHL). Lactate dehydrogenase B (LDHB) is a key glycolytic enzyme that catalyzes the interconversion of pyruvate and lactate. LDH activity and isoenzyme patterns are known to be changed with aging, but the role of LDHB in ARHL has not been studied yet. Here, we found that LDHB knockout mice showed hearing loss at high frequencies, which is the typical feature of ARHL. LDHB knockdown caused downregulation of mitochondrial functions in auditory cell line, University of Bristol/organ of Corti 1 (UB/OC1) with decreased NAD+ and increased hypoxia inducing factor-1α. LDHB knockdown also enhanced the death of UB/OC1 cells with ototoxic gentamicin treatment. On the contrary, the induction of LDHB expression caused enhanced mitochondrial functions, including changes in mitochondrial respiratory subunits, mitochondrial membrane potentials, ATP, and the NAD+/NADH ratio. Thus, we concluded that suppression of LDHB activity may be closely related with the early onset or progression of ARHL.
Highlights
Age-related hearing loss (ARHL) that occurs in response to aging is a universal disorder in modern society
Lactate dehydrogenase B (LDHB) deficiency significantly increased the sensitivity of University of Bristol/organ of Corti 1 (UB/OC1) cells to cisplatin and gentamicin (Fig. 7i). These results show that depletion of LDHB in mitochondria makes differentiated auditory cells much more vulnerable to oxidative stress and damage from reactive oxygen species (ROS) originating in the mitochondria, and suggest that downregulation of LDHB is a potential contributor to the progression of ARHL
It is well-known that pyruvate is the substrate of mitochondrial adenosine triphosphate (ATP) production and final product of glycolysis
Summary
Age-related hearing loss (ARHL) that occurs in response to aging is a universal disorder in modern society. ARHL is characterized by an age-associated defect in hearing function, which begins with an increased hearing threshold in the high-frequency region and spreads toward the low-frequency region. This process is characterized by the loss of hair cells and spiral ganglion neurons (SGNs) in the cochlea with age[1,2,3]. Studies on mitochondria isolated from human muscle biopsies or rodent muscles support the existence of an intrinsic, aging-dependent mitochondrial defect associated with adenosine triphosphate (ATP) production[6]. Mitochondria are the main source of ATP and a direct intrinsic byproduct of this ATP production is reactive oxygen species (ROS). During aging, damaged mitochondria induced less ATP production and aberrant ROS generation, leading to oxidative stress and cellular senescence[7]
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