Age-associated decline in Nrf2 signaling and associated mtDNA damage may be involved in the degeneration of the auditory cortex: Implications for central presbycusis

Abstract

Central presbycusis is the most common sensory disorder in the elderly population, however, the underlying molecular mechanism remains unclear. NF-E2-related factor 2 (Nrf2) is a key transcription factor in the cellular response to oxidative stress, however, the role of Nrf2 in central presbycusis remains to be elucidated. The aim of the present study was to investigate the pathogenesis of central presbycusis using a mimetic aging model induced by D-galactose (D-gal) in vivo and in vitro. The degeneration of the cell was determined with transmission electron microscopy, terminal deoxynucleotidyl transferase-mediated deoxyuridine 5'-triphosphate nick-end labeling staining, and senescence-associated β-galactosidase staining. The expression of protein was detected by western blotting and immunofluorescence. The quantification of the mitochondrial DNA (mtDNA) 4,834-base pair (bp) deletion and mRNA was detected by TaqMan quantitative polymerase chain reaction (qPCR) and reverse transcription-qPCR respectively. Cell apoptosis and intracellular ROS in vitro were determined with flow cytometry. The levels of nuclear Nrf2, and the mRNA levels of Nrf2-regulated antioxidant genes, were downregulated in the auditory cortex of aging rats, which was accompanied by an increase in 8-hydroxy-2'-deoxyguanosine formation, an accumulation of mtDNA 4,834-bp deletion, and neuron degeneration. In addition, oltipraz, a typical Nrf2 activator, was found to protect cells against D-gal-induced mtDNA damage and mitochondrial dysfunction by activating Nrf2 target genes in vitro. It was also observed that activating Nrf2 with oltipraz inhibited cell apoptosis and delayed senescence. Taken together, the data of the present study suggested that the age-associated decline in Nrf2 signaling activity and the associated mtDNA damage in the auditory cortex may be implicated in the degeneration of the auditory cortex. Therefore, the restoration of Nrf2 signaling activity may represent a potential therapeutic strategy for central presbycusis.

NRF2 as a Therapeutic Target in Neurodegenerative Diseases

“…A role has also been described for NRF2 in maintaining mitochondrial integrity and regulating mitochondrial biogenesis. It has been reported that NRF2 activation protects mitochondria by opening the mitochondrial permeability transition pore (Lee et al, 2000;Greco and Fiskum, 2010;Greco et al, 2011) and that declining NRF2 signaling is associated with increased damage to mitochondrial DNA (mtDNA; Li et al, 2018). In addition, NRF2 activation modulates the expression of ATP synthase subunit a and NDUFA4, two components of the electron transport chain (Abdullah et al, 2012;Agyeman et al, 2012), and mice in which NRF2 has been deleted have lower mtDNA globally than wild-type (WT) mice (Zhang et al, 2013).…”

PQM130, a Novel Feruloyl–Donepezil Hybrid Compound, Effectively Ameliorates the Cognitive Impairments and Pathology in a Mouse Model of Alzheimer’s Disease

“…They also speculated that “Nrf2 might act as a molecular link between brain aging and AD” (Branca et al, 2017). Numerous laboratories supported this hypothesis showing that Nrf2 activity decreased with aging (Suh et al, 2004; Zhang et al, 2015; Li et al, 2018). Moreover, Nrf2 activity is strictly related to tau pathology, enhancing the link between Nrf2 and AD (Lastres-Becker et al, 2014).…”

Activation of the NRF2 pathway in Keap1-knockdown mice attenuates progression of age-related hearing loss

“…In contrast, changes in ROS elimination caused by aging are likely to vary depending on the tissues and contexts. Antioxidant defense activities were reported to decrease in cochlea and brain during aging 68,69 ; however, other reports showed that antioxidant defense activities in the muscle and brain remained unchanged or increased 65,[70][71][72] . In this study, we found that NRF2 pathway activity was not changed in the cochleae for as long as 12 months.…”