ROS-Induced Activation of DNA Damage Responses Drives Senescence-Like State in Postmitotic Cochlear Cells: Implication for Hearing Preservation

Benkafadar, Nesrine; François, Florence; Affortit, Corentin; Casas, François; Ceccato, Jean Charles; Menardo, Julien; Venail, F.; Malfroy-Camine, Bernard; Puel, Jean–Luc; Wang, Jing

doi:10.1007/s12035-019-1493-6

Cited by 70 publications

(70 citation statements)

References 65 publications

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“…Consistent with these findings, our recent results revealed that sub-lethal concentrations of hydrogen peroxide (H 2 O 2 )-exposure initiated a DNA damage response together with increased levels of key hallmarks of senescent cells, including increased expression levels of p21, and positive senescence-associated β-galactosidase labeling cells in cochlear explants in culture, together with increased inflammatory markers such as p38 and p-p38. Furthermore, high amounts of DNA damage and senescence-like features were observed in the cochlear tissues of SAMP8 mice during aging and were correlated with the accelerated ARHL observed in SAMP8 mice [70]. In addition, an accumulation of age pigment or lipofuscin was observed in the cytoplasm of spiral ganglion neurons of SAMP8 mice [59].…”

Section: Senescence-like Phenotypementioning

confidence: 78%

“…These displayed mitochondrial morphology damage, reduced mitochondrial membrane potentials, an imbalance of mitochondrial fusion/fission, and an impaired mitochondrial respiratory capacity [69]. Furthermore, using an H 2 O 2 exposed cochlear explant in culture and adult SAMP8 mice in vivo, we demonstrated that ROS-induced DNA damage responses drive cochlear cell senescence and contribute to accelerated ARHL [70].…”

Section: Dna Damage and Dna Damage Responsesmentioning

confidence: 83%

“…Finally, the synthetic superoxide dismutase/catalase mimetic EUK-207 reduced age-related loss of hearing and hair-cell degeneration in senescence-accelerated mouse-prone 8 mice [70] (Figures 4 and 5). Coenzyme Q10, or its analog, coenzyme Q10-Ter, which are important molecules implicated in mitochondrial energy production and protection of mitochondrial membrane proteins, lipids, and DNA from oxidative damage, prevents age-related hearing loss [62].…”

Section: Antioxidants Free Radical Scavengers and Anti-inflammatoriesmentioning

confidence: 96%

“…Representative scanning electron micrographs showing the basal regions of cochleae from Manitol-treated (left panel) and EUK-207-treated (right panel) SAMP8 mice after three months. Scale bar = 15 µm (Adapted from Benkafadar et al[70]).…”

mentioning

confidence: 99%

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Presbycusis: An Update on Cochlear Mechanisms and Therapies

Wang

Puel

2020

JCM

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156

125

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Age-related hearing impairment (ARHI), also referred to as presbycusis, is the most common sensory impairment seen in the elderly. As our cochlea, the peripheral organ of hearing, ages, we tend to experience a decline in hearing and are at greater risk of cochlear sensory-neural cell degeneration and exacerbated age-related hearing impairments, e.g., gradual hearing loss, deterioration in speech comprehension (especially in noisy environments), difficulty in the localization sound sources, and ringing sensations in the ears. However, the aging process does not affect people uniformly; nor, in fact, does the aging process appear to be uniform even within an individual. Here, we outline recent research into chronological cochlear age in healthy people, and exacerbated hearing impairments during aging due to both extrinsic factors including noise and ototoxic medication, and intrinsic factors such as genetic predisposition, epigenetic factors, and aging. We review our current understanding of molecular pathways mediating ARHL and discuss recent discoveries in experimental hearing restoration and future prospects.

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Section: Senescence-like Phenotypementioning

confidence: 78%

Section: Dna Damage and Dna Damage Responsesmentioning

confidence: 83%

Section: Antioxidants Free Radical Scavengers and Anti-inflammatoriesmentioning

confidence: 96%

mentioning

confidence: 99%

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Presbycusis: An Update on Cochlear Mechanisms and Therapies

Wang

Puel

2020

JCM

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156

125

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“…Senescence-associated b-galactosidase (SA-b-Gal) activity staining The cultured CBM senescence assay was performed by staining for SA-b-Gal activity, and the pH of the SA-b-Gal staining solution was 6, following the manufacturer's instructions and the steps outlined in previous reports (Benkafadar et al 2019;Zhao et al 2013). Briefly, the cell culture medium was removed and the CBM washed once with phosphate-buffered saline (PBS).…”

Section: Cbm Primary Culture and Senescence Model Induced By D-galmentioning

confidence: 99%

d-Galactose-induced oxidative stress and mitochondrial dysfunction in the cochlear basilar membrane: an in vitro aging model

Guo

Zhan

et al. 2020

Biogerontology

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The cochlear basilar membrane (CBM) contains inner hair cells and outer hair cells that convert sound waves into electrical signals and transmit them to the central auditory system. Cochlear aging, the primary reason of age-related hearing loss, can reduce the signal transmission capacity. There is no ideal in vitro aging model of the CBM. In this study, we cultured the CBM, which was dissected from the cochlea of the C57BL/6 mice 5 days after birth, in a medium containing 20 mg/mL, 40 mg/mL, or 60 mg/ mL D-galactose (D-gal). Compared with the control group, the levels of senescence-associated b-galactosidase were increased in a concentration-dependent manner in the CBM of the D-gal groups. In addition, levels of the mitochondrial superoxide and patterns of an age-related mitochondrial DNA3860-bp deletion were significantly increased. The ATP levels and the membrane potential of the mitochondrial were significantly decreased in the CBM of the D-gal groups compared with the control group. Furthermore, in comparison with the control group, damaged hair cell stereocilia and a loss of inner hair cell ribbon synapses were observed in the CBM of the D-gal groups. A loss of hair cells and activation of caspase-3-mediated outer hair cell apoptosis were also observed in the CBM of the high-dose D-gal group. These insults induced by D-gal in the CBM in vitro were similar to the ones that occur in cochlear natural aging in vivo. Thus, we believe that this is a successful in vitro aging model using cultured CBM. These results demonstrate

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PARP inhibitor rescues hearing and hair cell impairment in Cx26‐null mice

Wang,

Chen,

Qiu

et al. 2023

VIEW

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GJB2 (encoding connexin26, Cx26) mutation is the most common genetic cause of hereditary deafness. Cochlear sensory hair cell (HC) death is the core pathologic phenomenon of GJB2‐related deafness. However, mechanism‐based therapy is still obscure. A targeted‐cell conditional Gjb2 knockout mouse model was established in which the Cx26 in Deiters cells and pillar cells were knocked out at birth. We explored the mechanism of HC death caused by deficiency of GJB2 in supporting cells (SCs), which exhibited moderate deafness, early HC death without SCs, and a decrease in distortion product otoacoustic emission. Here, a DNA damage response was observed in HCs during the onset of hearing loss. Apoptosis, necroptosis, and ferroptosis do not contribute to the death of HCs. We identified and demonstrated that parthanatos, a poly‐(ADP‐ribose) polymerase (PARP)‐dependent and caspase‐independent form of cell death, is a mechanism of HC degeneration. Furthermore, we observed that the use of PARP inhibitors effectively alleviated both deafness and HC loss. Our study reveals the specific mechanism of HC death caused by GJB2 deficiency. These findings demonstrate that targeting parthanatos is an HC protective strategy in the prevention of GJB2‐related hereditary deafness.

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ROS-Induced Activation of DNA Damage Responses Drives Senescence-Like State in Postmitotic Cochlear Cells: Implication for Hearing Preservation

Cited by 70 publications

References 65 publications

Presbycusis: An Update on Cochlear Mechanisms and Therapies

Presbycusis: An Update on Cochlear Mechanisms and Therapies

d-Galactose-induced oxidative stress and mitochondrial dysfunction in the cochlear basilar membrane: an in vitro aging model

PARP inhibitor rescues hearing and hair cell impairment in Cx26‐null mice

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