Abstract
Intracellular accumulation of wild type tau is a hallmark of sporadic Alzheimer's disease (AD). However, the molecular mechanisms underlying tau toxicity is not fully understood. Here, we detected mitophagy deficits evidenced by the increased levels of mitophagy markers, including COX IV, TOMM20, and the ratio of mtDNA to genomic DNA indexed as mt-Atp6/Rpl13, in the AD brains and in the human wild type full-length tau (htau) transgenic mice. More interestingly, the mitophagy deficit was only shown in the AD patients who had an increased total tau level. Further studies demonstrated that overexpression of htau induced mitophagy deficits in HEK293 cells, the primary hippocampal neurons and in the brains of C57 mice. Upon overexpression of htau, the mitochondrial membrane potential was increased and the levels of PTEN-induced kinase 1 (PINK1) and Parkin decreased in the mitochondrial fraction, while upregulation of Parkin attenuated the htau-induced mitophagy deficits. Finally, we detected a dose-dependent allocation of tau proteins into the mitochondrial outer membrane fraction along with its cytoplasmic accumulation. These data suggest that intracellular accumulation of htau induces mitophagy deficits by direct inserting into the mitochondrial membrane and thus increasing the membrane potential, which impairs the mitochondrial residence of PINK1/Parkin. Our findings reveal a novel mechanism underlying the htau-induced neuronal toxicities in AD and other tauopathies.
Highlights
Mitochondria play crucial roles in energy production, the synthesis of key metabolites, apoptosis regulation, calcium buffering, and generation of endogenous reactive oxygen species [1, 2]
We show that intracellular accumulation of human wild type full-length tau, as seen in the sporadic Alzheimer’s disease (AD) brains, induces mitophagy deficits, with the mechanisms involving a direct insertion of htau into the outer membrane fractions of mitochondria, an increased mitochondrial membrane potential and an impaired mitochondrial residence of PTENinduced kinase 1 (PINK1)/Parkin
We find that intracellular accumulation of human wild type www.impactjournals.com/oncotarget full-length tau, as seen in sporadic AD brains, results in mitophagy deficits
Summary
Mitochondria play crucial roles in energy production, the synthesis of key metabolites, apoptosis regulation, calcium buffering, and generation of endogenous reactive oxygen species [1, 2]. Tau phosphorylation can antagonize cell apoptosis with the mechanisms involving Bcl-2 and caspase-3 in mitochondria [24,25,26], while expression of fusion proteins attenuates apoptosis [27] These observations suggest that intracellular accumulation of tau may cause neurodegeneration through disrupting mitochondrial functions, but the direct evidence for the role of wild type full-length tau in the mitophagy is still lacking. We show that intracellular accumulation of human wild type full-length tau, as seen in the sporadic AD brains, induces mitophagy deficits, with the mechanisms involving a direct insertion of htau into the outer membrane fractions of mitochondria, an increased mitochondrial membrane potential and an impaired mitochondrial residence of PINK1/Parkin
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