TUFM Is Involved In Alzheimer’s Disease-like Pathologies That Are Associated With ROS

Mitochondrial Tu translation elongation factor(TUFM or EF-Tu)is part of the mitochondrial translation machinery.It is reported that TUFM expression is reduced in the brain of Alzheimer’s disease(AD),suggesting that TUFM might play a role in the pathophysiology.In this study,we found that TUFM protein level was decreased in the hippocampus and cortex especially in the aged APP/PS1 mice,an animal model of AD.In HEK cells that stably express full-length human amyloid-β precursor protein(HEK-APP),TUFM knockdown or overexpression increased or reduced the protein levels of β-amyloid protein(Aβ)and β-amyloid converting enzyme 1(BACE1),respectively.TUFM-mediated reduction of BACE1 was attenuated by translation inhibitor cycloheximide(CHX)orα-[2-[4-(3,4-Dichlorophenyl)-2-thiazolyl]hydrazinylidene]-2-nitro-benzene propanoic acid(4EGI1),and in cells overexpressing BACE1 constructs deleting the 5’ untranslated region(5’UTR).TUFM silencing increased the half-life of BACE1 m RNA,suggesting that RNA stability was affected by TUFM.In support,transcription inhibitor Actinomycin D(Act D)and silencing of nuclear factor κB(NFκB)failed to abolish TUFM-mediated regulation of BACE1 protein and m RNA.We further found that the mitochondria-targeted antioxidant TEMPO diminished the effects of TUFM on BACE1,suggesting that reactive oxygen species(ROS)played an important role.Indeed,cellular ROS levels were affected by TUFM knockdown or overexpression,and TUFM-mediated regulation of apoptosis and Tau phosphorylation at selective sites was attenuated by TEMPO.Collectively,TUFM protein levels were decreased in APP/PS1 mice.TUFM is involved in AD pathology by regulating BACE1 translation,apoptosis and Tau phosphorylation,in which ROS plays an important role.