• 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • Taken together CYTOR may present a protective effect in


    Taken together, CYTOR may present a protective effect in cardiac hypertrophy through regulating miR-155 and downstream IKKi and NF-κB signaling pathways, most likely via the mechanism that CYTOR functions as a ceRNA for miR-155 to reduce miR-155-induced suppression of IKBKE, thus affecting downstream IKKi and NF-κB signaling.
    Transparency document
    Introduction Huntington's disease (HD) is a fatal and inherited neurodegenerative disorder that progresses for 15–20 years after initial onset [1]. The main cause of HD is the expanded CAG repeats encoding polyglutamine (polyQ) in the N-terminus of the huntingtin (Htt) protein [2,3]. The genetic cause of HD (mutant Htt, mtHtt) has been identified for >20 years. However, the underlying mechanisms occurring in HD remain elusive. Accumulating evidence suggests that mitochondrial dysfunction plays an important role in the pathogenesis of HD [2]. For instance, mtHtt associates with the outer mitochondrial membrane in different HD models, resulting in mitochondrial permeability transition pore opening, calcium disturbance, reduced ATP production, mitochondrial membrane potential loss, increased ROS production, and release of cytochrome c [4]. PGC-1α is a transcription co-activator that regulates the genes involved in mitochondrial biogenesis [5]. mtHtt interacts with PGC-1α and suppresses its activity in HD mouse striatal L-Glutamine as well as in HD transgenic mouse models [6]. Mitochondria are highly dynamic organelles, and the balance between fission and fusion is important for maintaining normal mitochondrial function. mtHtt interacts with Drp1, the master regulator of mitochondrial fission, leading to Drp1 hyperactivation and mitochondrial fragmentation [7]. We previously reported that treatment with peptide P110 (a specific peptide inhibitor of Drp1) decreased mtHtt-induced mitochondrial fragmentation, corrected defects in mitochondrial function, and reduced neuronal cell death in both in vivo and in vitro HD models [8]. Moreover, in vivo and in vitro HD models exhibit accelerated mitochondrial outer membrane protein degradation and excessive mitophagy [9,10]. Collectively, these findings highlight the mitochondria as a promising therapeutic target for the treatment of HD. When damaged protein accumulates in the mitochondrial matrix and exceeds the maximal capacity of the protein folding apparatus, the defense mechanism called the mitochondrial unfolded protein response (UPRmt) is activated to process the cellular stress occurring in the mitochondrial matrix [11,12]. Upon UPRmt activation, mitochondrial chaperones are induced and imported into mitochondria to refold the damaged proteins [11,12]. On the other hand, the mitochondrial matrix protease Clpp (ATP-dependent Clp protease proteolytic subunit) cleaves unfolded or misfolded proteins inside the mitochondria into polypeptides [13,14]. In worms, activating transcription factor associated with stress-1 (ATFS-1), a leucine zipper transcription factor, is imported into the mitochondrial matrix for degradation under normal physiological conditions [15]. Damaged proteins are then cleaved into short peptides, which are exported to the cytosol via the inner membrane transporter HAF-1, leading to ATFS-1 nuclear translocation [13,15]. Consequently, ATFS1 facilitates transcriptional activation of UPRmt target genes [15]. It has recently been reported that the UPRmt is activated in diseases such as Friedreich's ataxia [16], spastic paraplegia [17], cancer [18,19], and aging [20]. However, little is known about the role of the UPRmt in the pathogenesis of HD. ABCB10 is one of the components of the UPRmt pathway in mammalian cells [21]. In this study, we found that mtHtt suppressed the expression of ABCB10 in various HD models by impairing its mRNA stability. Deletion of ABCB10 induced ROS production and cell death in HD mouse striatal cells. Moreover, ABCB10 was required for CHOP activation under mitochondrial stress. We also showed that HSP60 and Clpp, two downstream genes of CHOP [22], were decreased in HD cells. These data suggest a dysregulation of UPRmt in HD, revealing a novel mechanism of mitochondrial dysfunction in the pathogenesis of this devastating disease.