Mutant huntingtin inhibits the mitochondrial unfolded protein response by impairing ABCB10 mRNA stability

Biochimica Et Biophysica Acta. Molecular Basis of Disease
Zixing FuXing Guo

Abstract

Numerous studies have shown that mitochondrial dysfunction contributes to consequential phenotypes of Huntington's disease (HD), a fatal and inherited neurodegenerative disease caused by the expanded CAG repeats in the N-terminus of the huntingtin (Htt) gene. To maintain proper function, mitochondria develop a dedicated protein quality control mechanism by activating a stress response termed the mitochondrial unfolded protein response (UPRmt). Defects in the UPRmt have been linked to aging and are also associated with neurodegenerative diseases. However, little is known about the role of the UPRmt in HD. In this study, we find that ABCB10, a mitochondrial transporter involved in the UPRmt pathway, is downregulated in HD mouse striatal cells, HD patient fibroblasts, and HD R6/2 mice. Deletion of ABCB10 causes increased mitochondrial reactive oxygen species (ROS) production and cell death, whereas overexpression of ABCB10 reduces these aberrant events. Moreover, the mitochondrial chaperone HSP60 and mitochondrial protease Clpp, two well-established markers of the UPRmt, are reduced in the in vitro ABCB10-deficienct HD models. CHOP, a key transcription factor of HSP60 and Clpp, is regulated by ABCB10 in HD mouse striatal cells. Fu...Continue Reading

Citations

Nov 30, 2019·Frontiers in Aging Neuroscience·Hao MengJue-Pu Zhou
Mar 25, 2020·International Journal of Molecular Sciences·Wioletta Rozpędek-KamińskaIreneusz Majsterek
Dec 22, 2020·Free Radical Biology & Medicine·Li ZhuLinxi Chen
Jun 12, 2021·Disease Models & Mechanisms·Marlies P RossmannLeonard I Zon
Jul 4, 2021·Biochemical and Biophysical Research Communications·Di HuXin Qi

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