The Effect Of PINK1/Parkin-mediated Mitophagy On Cisplatin Induced PC12 Cells Neurotoxicity

Chemotherapy-induced peripheral neuropathy(CIPN)is a common dosedependent side effect of most chemotherapeutic agents.In addition to affecting the quality of life for cancer patients,CIPN also lead to reduction or even cessation of anticancer therapy.Therefore,exploring the potential mechanism and novel therapeutic strategies are becoming the research hotspots.The mechanism of CIPN remains elusive,and it is likely to involve direct impacts on sensory neuron viability as well as mitochondria-specific consequences.Mitochondria provide energy to neurons and preserve several interrelated pathways for cellular processes including the apoptotic signaling pathways and reactive oxygen species(ROS)generation.Mitochondria are the primary and early targets in cisplatininduced neurotoxicity.The morphological changes and dysfunction of mitochondria,including insufficient ATP production,increased ROS production,and potential membrane collapse have been identified after cisplatin treatment both in vivo and in vitro.Since the damaged or dysfunctional mitochondria contribute to CIPN,the elimination of those impaired organelles may exert a protective effect in CIPN.Mitophagy is a selective removal of defective mitochondria through autophagy,which plays a crucial role in the preservation of a healthy mitochondria pool for cellular homeostasis.Autophagy and mitophagy have highly similar molecular pathways to form autophagosomes and autolysosomes.However,as a most documented mitophagyspecific signaling cascade,the PINK1/Parkin pathway can initiate recruitment of autophagy machinery and facilitate engulfment of damaged mitochondria into autophagosomes.Mitophagy impairment is linked to variable pathological conditions,such as neurodegenerative diseases,inflammation,and cancer.Recent studies showed that PINK1/Parkin-mediated mitophagy could protect cisplatin-induced kidney injury.The effect of mitophagy on CIPN is still unknown.Thus,the purpose of the present study is to determine the mitophagy status and its effects on mitochondrial function and cell apoptosis after cisplatin treatment using an in vitro model of CIPN.Here,we demonstrated that cisplatin could activate PINK1/Parkin-mediated mitophagy in PC12 cells.Moreover,confocal microscopy analysis of autophagic flux revealed that cisplatin inhibited the late stage of the autophagic process.Next,we investigated the effects of PINK1/Parkin-mediated mitophagy on cisplatin-induced neurotoxicity by concentrating on mitochondrial function and apoptosis.We found that knockdown of Parkin suppressed cisplatin-induced mitophagy and aggravated cisplatin-induced depolarization of mitochondria,cellular ATP deficits,reactive oxygen species outburst,and apoptosis,while Parkin overexpression enhanced mitophagy and reversed these effects.Our results implicate the protective role of PINK1/Parkin-regulated mitophagy against cisplatin-related neurotoxicity,suggesting that therapeutical enhancement of mitophagy is a potential intervention of cisplatininduced peripheral neuropathies.Furthermore,the interference of cisplatin with autophagosome-lysosome fusion may partly be responsible for cisplatin-induced neurotoxicity.