PINK1 Protects Auditory Hair Cells and Spiral Ganglion Neurons from Cisplatin-induced Ototoxicity via Inducing Autophagy and Inhibiting JNK Signaling Pathway

Yang, Qianqian; Sun, Gaoying; Yin, Haiyan; Li, Hongrui; Cao, Zhixin; Wang, Jinghan; Zhou, Meijuan; Wang, Haibo; Li, Jianfeng

doi:10.1016/j.freeradbiomed.2018.02.025

Cited by 56 publications

(34 citation statements)

References 37 publications

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“…58 Parkin results in the accumulation of dysfunctional mitochondria that release ROS, thereby increasing the oxidative stress that is involved in the pathogenesis of several diseases. [61][62][63] We found that PINK1 and Parkin protein levels and mitochondrial Parkin translocation were increased in human NP cells upon compression, which was accompanied by increased colocalization of LC3 and Tom20, indicating mitophagy initiation. However, after deeper investigation, we found that the protein level of p62 was remarkably upregulated and lysosomal quenching of GFP fluorescence was compromised,…”

Section: Discussionmentioning

confidence: 79%

The mitochondria‐targeted anti‐oxidant MitoQ protects against intervertebral disc degeneration by ameliorating mitochondrial dysfunction and redox imbalance

et al. 2020

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Objective Mitochondrial dysfunction, oxidative stress and nucleus pulposus (NP) cell apoptosis are important contributors to the development and pathogenesis of intervertebral disc degeneration (IDD). Here, we comprehensively evaluated the effects of mitochondrial dynamics, mitophagic flux and Nrf2 signalling on the mitochondrial quality control, ROS production and NP cell survival in in vitro and ex vivo compression models of IDD and explored the effects of the mitochondria‐targeted anti‐oxidant MitoQ and its mechanism. Material and methods Human NP cells were exposed to mechanical compression to mimic pathological conditions. Results Compression promoted oxidative stress, mitochondrial dysfunction and NP cell apoptosis. Mechanistically, compression disrupted the mitochondrial fission/fusion balance, inducing fatal fission. Concomitantly, PINK1/Parkin‐mediated mitophagy was activated, whereas mitophagic flux was blocked. Nrf2 anti‐oxidant pathway was insufficiently activated. These caused the damaged mitochondria accumulation and persistent oxidative damage. Moreover, MitoQ restored the mitochondrial dynamics balance, alleviated the impairment of mitophagosome‐lysosome fusion and lysosomal function and enhanced the Nrf2 activity. Consequently, damaged mitochondria were eliminated, redox balance was improved, and cell survival increased. Additionally, MitoQ alleviated IDD in an ex vivo rat compression model. Conclusions These findings suggest that comodulation of mitochondrial dynamics, mitophagic flux and Nrf2 signalling alleviates sustained mitochondrial dysfunction and oxidative stress and represents a promising therapeutic strategy for IDD; furthermore, our results provide evidence that MitoQ might serve as an effective therapeutic agent for this disorder.

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Section: Discussionmentioning

confidence: 79%

The mitochondria‐targeted anti‐oxidant MitoQ protects against intervertebral disc degeneration by ameliorating mitochondrial dysfunction and redox imbalance

et al. 2020

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“…It has been well documented that PINK1 can ameliorate the oxidative stress and mitochondrial damage in multiple cells . Recently, we have demonstrated that PINK1 widely exists in SGNs and possesses the protective effect in cisplatin‐induced SGNs injury through inhibiting apoptosis, which implies that PINK1 plays an important role on cisplatin‐induced SGN damage . Moreover, in other neuronal cells, PINK1 has been reported to regulate the apoptosis‐related gene to increase cell survival .…”

Section: Introductionmentioning

confidence: 90%

Paeoniflorin protects spiral ganglion neurons from cisplatin‐induced ototoxicity: Possible relation to PINK1/BAD pathway

Man

et al. 2019

J Cellular Molecular Medi

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The objective of this study was to elucidate whether paeoniflorin (PF) exerted an effect on cisplatin‐induced spiral ganglion neuron (SGN) damage, with special attention given to the role of PINK1/BAD pathway in this process. Middle cochlear turn culture and C57BL/6 mice were utilized to identify the character of PF in vitro and in vivo. We found that cisplatin treatment led to SGN damage, in which reactive oxygen species (ROS) generation increased, PINK1 expression decreased, BAD accumulation on mitochondria raised and mitochondrial apoptotic pathway activated. Conversely, we demonstrated that PF pre‐treatment obviously mitigated cisplatin‐induced SGN damage. Mechanistic studies showed that PF could reduce ROS levels, increase PINK1 expression, decrease the BAD accumulation on mitochondria and, thus, alleviate the activated mitochondrial apoptosis in SGNs caused by cisplatin. Overall, the findings from this work reveal the important role of PF and provide another strategy against cisplatin‐induced ototoxicity.

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“…Chika et al demonstrated that oral administration of low‐dose rapamycin induced autophagy activation in cochlear outer sulcus cells, suggesting that rapamycin could be a feasible drug to manipulate inner ear cells 147 . Phosphatase and tensin homolog‐induced putative kinase 1 also protected hair cells from cisplatin‐induced ototoxicity following induction of autophagy 148 …”

Section: Autophagic Pathways In Hlmentioning

confidence: 99%

Programmed cell death pathways in hearing loss: A review of apoptosis, autophagy and programmed necrosis

Kong

et al. 2020

Cell Proliferation

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Programmed cell death (PCD)—apoptosis, autophagy and programmed necrosis—is any pathological form of cell death mediated by intracellular processes. Ototoxic drugs, ageing and noise exposure are some common pathogenic factors of sensorineural hearing loss (SNHL) that can induce the programmed death of auditory hair cells through different pathways, and eventually lead to the loss of hair cells. Furthermore, several mutations in apoptotic genes including DFNA5, DFNA51 and DFNB74 have been suggested to be responsible for the new functional classes of monogenic hearing loss (HL). Therefore, in this review, we elucidate the role of these three forms of PCD in different types of HL and discuss their guiding significance for HL treatment. We believe that further studies of PCD pathways are necessary to understand the pathogenesis of HL and guide scientists and clinicians to identify new drug targets for HL treatment.

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PINK1 Protects Auditory Hair Cells and Spiral Ganglion Neurons from Cisplatin-induced Ototoxicity via Inducing Autophagy and Inhibiting JNK Signaling Pathway

Cited by 56 publications

References 37 publications

The mitochondria‐targeted anti‐oxidant MitoQ protects against intervertebral disc degeneration by ameliorating mitochondrial dysfunction and redox imbalance

The mitochondria‐targeted anti‐oxidant MitoQ protects against intervertebral disc degeneration by ameliorating mitochondrial dysfunction and redox imbalance

Paeoniflorin protects spiral ganglion neurons from cisplatin‐induced ototoxicity: Possible relation to PINK1/BAD pathway

Programmed cell death pathways in hearing loss: A review of apoptosis, autophagy and programmed necrosis

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