Inhibition of mitochondrial protein import by mutant huntingtin(Nat Neurosci. 2014;17(6):822-31)

報告日期: 2015/11/27
報告時間: 4:00/4:50
報告學生: 林秀蓮
講評老師: 姜學誠
附件下載: 下載[1531-1443056149-1.pdf] 

Inhibition of mitochondrial protein import by mutant huntingtin

Hiroko Yano et al.

Nature Neuroscience 17(6): 822-831, 2014

Time: 16:00-16:50, Nov 27 2015         Speaker: Lin, Hsiu-Lien (林秀蓮)                 

Venue: Room 602                               Commentator: Dr. Chinag, Hsueh-Cheng (姜學誠)


Huntington’s disease (HD) is an inherited neurodegenerative disorder which is resulted from an abnormal expansion of CAG repeats in the HTT gene, resulting in expanded polyglutamine (polyQ) in the mutant huntingtin (mHtt) protein. It has been reported that mHtt directly affects mitochondrial functions, and leads to neuronal loss in HD. However, the mechanism between mHtt and mitochondrial dysfunctions in HD is still unknown. Mitochondria contain approximately 1,500 different proteins which are essential for maintaining normal mitochondrial functions. Only ~1% of mitochondrial proteins are encoded by mitochondrial genome. In other words, more than ~99% mitochondrial proteins are synthesized in cytosolic ribosomes, and then translocated into mitochondria by the protein import machinery. These are crucial for the cell viability. Therefore, the authors hypothesized that mitochondrial dysfunction in HD might be caused by the blockade of mitochondrial protein import pathway. The authors applied GST pull-down assay to identify an interaction between mHtt and the TIM23 mitochondria protein import complex. Furthermore, the authors utilized a radiolabeled pOTC, precursor matrix protein, to examine protein import activity, and showed mHtt specifically associated with TIM23 complex and directly inhibit protein import in mitochondria. They also observed an early defect of protein import in neuronal mitochondria of forebrain, not liver mitochondria, suggesting that deficient mitochondrial protein import is an early and tissue-specific event in HD. Finally, the authors proved increased mitochondrial protein import by overexpression TIM23 complex in mHtt-expressing neurons can rescue neuronal death. Taken together, these findings indicated the evidence of a direct link between mHtt, mitochondria dysfunction and neuronal pathology in HD.


  1. Harbauer, A.B., Zahedi, R.P., Sickmann, A., Pfanner, N., and Meisinger, C. (2014). The protein import machinery of mitochondria-a regulatory hub in metabolism, stress, and disease. Cell metabolism 19, 357-372.
  2. Reddy, P.H., and Shirendeb, U.P. (2012). Mutant huntingtin, abnormal mitochondrial dynamics, defective axonal transport of mitochondria, and selective synaptic degeneration in Huntington's disease. Biochimica et biophysica acta 1822, 101-110.