论文部分内容阅读
Intracellular accumulation of tau protein,low energy metabolism and mitochondrial dysfunction are core features in the pathophysiology of sporadic Alzheimers disease(AD),however,the cellular mechanism whereby tau accumulation links the abnormal energy metabolism is poorly understood.We found that overexpression of human wild-type full-length tau(termed htau)rendered the cells more resistant to the exogenously induced-apoptosis.Tau accumulation disrupted mitochondrial dynamics by enhancing fusion and induced their perinuclear accumulation in HEK293 cells and in rat primary hippocampal neurons.The htau accumulation at later stage inhibited mitochondrial functions shown by the decreased ATP level and the ratio of ATP/ADP and as well as a decreased complex I activity.Simultaneously,the cell viability was decreased with retraction of the cellular/neuronal processes.Further studies demonstrated that the htau accumulation increased fusion proteins,including OPA1 and mitofusins(Mfn1,Mfn2)and reduced the ubiquitination of Mfn2.Downregulation of the mitofusins by shRNA to~45%or~52%of the control levels attenuated the htau-enhanced mitochondrial fusion and restored the functions,while downregulation of OPA1 to~50%of the control level did not show rescue effects.With a dose-dependent allocation of tau proteins into the mitochondrial outer membrane fraction,mitophagy deficits,shown by the increased,mitochondrial membrane potential was increased and mitophagy deficits was shown by the increased levels of mitophagy markers,including COX Ⅳ,TOMM20,and the ratio of mtDNA to genomic DNA indexed as mt-Atp6/Rpl13.Finally,mitochondrial dysfunction and mitophagy deficits were also observed in the brains of htau transgenic mice.Taken together,our data demonstrate that htau accumulation decreases cell viability and causes degeneration via enhancing mitofusin-associated mitochondrial fusion and mitophagy deficits,which provides new insights into the molecular mechanisms underlying tauopathies.