PINK1 Regulates The Progression Of Mitophagy By Phosphorylating A Mitochondrial Protein

Parkinson’s disease(PD)is a typical neurodegenerative disease.The major pathologic hallmark of PD is that most of dopamine neurons die in the pars compacta of substantia nigra,with less production of dopamine in the striatum.The causes of neuronal death in PD remain elusive.Researches have showed that the morphological abnormality and dysfunction of mitochondrial contribute to the pathogenesis of Parkinson’s disease.PTEN-induced putative kinase1(PINK1),as a neuroprotective kinase,play protective roles in a variety of neurodegenerative diseases such as Parkinson’s disease,alzheimer’s disease and huntington’s disease by improving mitochondrial function,reducing oxidative stress response,maintaining normal mitochondrial morphology and membrane potential,improving mitochondrial energy metabolism,and protecting cells against apoptosis.But the regulation mechanisms of PINK1 are still not completely clear.Using a tandem affinity chromatography-mass spectrometry in Drosophlia,we found a series of proteins assosiated to PINK1.A mitochondrial protein called TF1 appealled to us.Previously,we have demenstrated that TF1 and PINK1 are in a common protein complex and they interact both physically and genetically.More impotantly,in this study,we showed that PINK1 phospharylates TF1 and identified the phosphorylation site of TF1 by phosphorylation antibody.Intrestingly,we showed that the non-phosphorylated TF1 promotes mitochondrial autophagy.TF1 was found to interact with ATG5,however,phosphorylated TF1 bind to more ATG5 in mitochondria,indicating that PINK1 phosphorylates TF1 to reduce mitophagy and maintain the mitochondrial homeostasis depend on ATG5.Genetic experiments in drosophila showed that overexpressing of TF1 did not rescue the pathological phenotypes of Parkin deficiency and the vice versa,suggesting that PINK1 phosphorylates TF1 protein to regulate mitophagy in a Parkin-independant way.Thus,we found a new pathway in which PINK1 and TF1 regulate mitophagy,which provided novel insights into the molecular mechanism of mitophagy.Meanwhile,these findings may contribute to effective therapy for the pathagenesis of Parkinson’s disease and other neurodegenerative diseases.