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

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1865; no. 6; pp. 1428 - 1435
• Main Authors: Fu, Zixing, Liu, Fang, Liu, Chunyue, Jin, Beifang, Jiang, Yueqing, Tang, Mingliang, Qi, Xin, Guo, Xing
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2019
• Subjects: ABCB10; Animals; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Cell Death - genetics; Cell Line; Chaperonin 60 - genetics; Chaperonin 60 - metabolism; Corpus Striatum - metabolism; Corpus Striatum - pathology; Endopeptidase Clp - genetics; Endopeptidase Clp - metabolism; Fibroblasts - metabolism; Fibroblasts - pathology; Gene Expression Regulation; Humans; Huntingtin Protein - deficiency; Huntingtin Protein - genetics; Huntington Disease - genetics; Huntington Disease - metabolism; Huntington Disease - pathology; Huntington's disease; Mice; Mice, Transgenic; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial dysfunction; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Mitochondrial unfolded protein response; Mutation; Neurons - metabolism; Neurons - pathology; RNA Stability; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction; Transcription Factor CHOP - genetics; Transcription Factor CHOP - metabolism; Unfolded Protein Response; ABCB10; Mitochondrial dysfunction; Huntington's disease; Mitochondrial unfolded protein response
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2019.02.015

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. Furthermore, we find that mutant huntingtin (mtHtt) inhibits the mtUPR by impairing ABCB10 mRNA stability. These findings demonstrate a suppression of the UPRmt by mtHtt, suggesting that disturbance of mitochondrial protein quality control may contribute to the pathogenesis of HD. •ABCB10 is decreased in HD cell cultures and HD R6/2 mice, which in turn leads to inhibition of the UPRmt.•Overexpression of ABCB10 rescues the UPRmt related genes expression, improves mitochondrial function, and attenuates cell death in HD models.•Mutant Htt inhibits the UPRmt by impairing ABCB10 mRNA stability.