Mutant Huntingtin Inhibits The Mitochondrial Unfolded Protein Response By Impairing ABCB10 MRNA Stability

Huntington’s disease is caused by excessive amplification of the N-terminal CAG sequence of the Huntingtin gene,which is a lethal dominant genetic disease.Research reports had shown that mitochondrial dysfunction is one of the main pathological features of Huntington’s disease.When it comes to be stimulated by the external environment,the misfolded protein in the mitochondria exceeds its own load and cannot be degraded in time,which will activate the mitochondrial unfolded protein response(UPRmt)to maintain the mitochondrial protein balance.Research evidence showed that UPRmt is associated with a variety of diseases,such as aging and neurodegenerative diseases.Current studies have shown that literature reports on the regulatory mechanism of UPRmt are mostly focused on Caenorhabditis elegans.In mammals,its mechanism has not yet been fully clarified.The homologous gene ABCB10 of HAF-1 is a mitochondrial transporter which is involved in the UPRmt pathway.The study found that the protein expression of ABCB10 decreased in the striatum cells of HD mice,fibroblasts of HD patients and HD R6/2 mice.Knockdown of ABCB10 can increase the production of mitochondrial reactive oxygen species(ROS)and cause cell death,when overexpression of ABCB10 can reduce ROS production and cell death.The vitro experiments confirmed that when ABCB10 was knocked down in HD striatal cells,the m RNA expression of two recognized markers of UPRmt,namely mitochondrial molecular chaperone HSP60 and mitochondrial protease Clpp,also decreased.CHOP,as a key transcription factor of HSP60 and Clpp-related UPRmt pathway,is also regulated by ABCB10.In addition,we found that mutant huntingtin(mt HTT)gene inhibits UPRmt by impairing ABCB10 m RNA stability.These findings prove that mt HTT has an inhibitory effect on UPRmt,which suggesting that the disorder of mitochondrial protein quality control may be related to the pathogenesis of HD.