A role of mitochondrial complex II defects in genetic models of Huntington's disease expressing N-terminal fragments of mutant huntingtin

Abstract

Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of a CAG repeat encoding a polyglutamine tract in the huntingtin (Htt) protein. The mutation leads to neuronal death through mechanisms which are still unknown. One hypothesis is that mitochondrial defects may play a key role. In support of this, the activity of mitochondrial complex II (C-II) is preferentially reduced in the striatum of HD patients. Here, we studied C-II expression in different genetic models of HD expressing N-terminal fragments of mutant Htt (mHtt). Western blot analysis showed that the expression of the 30 kDa Iron–Sulfur (Ip) subunit of C-II was significantly reduced in the striatum of the R6/1 transgenic mice, while the levels of the FAD containing catalytic 70 kDa subunit (Fp) were not significantly changed. Blue native gel analysis showed that the assembly of C-II in mitochondria was altered early in N171-82Q transgenic mice. Early loco-regional reduction in C-II activity and Ip protein expression was also demonstrated in a rat model of HD using intrastriatal injection of lentiviral vectors encoding mHtt. Infection of the rat striatum with a lentiviral vector coding the C-II Ip or Fp subunits induced a significant overexpression of these proteins that led to significant neuroprotection of striatal neurons against mHtt neurotoxicity. These results obtained in vivo support the hypothesis that structural and functional alterations of C-II induced by mHtt may play a critical role in the degeneration of striatal neurons in HD and that mitochondrial-targeted therapies may be useful in its treatment.

mRNA Expression Levels of PGC-1α in a Transgenic and a Toxin Model of Huntington’s Disease

“…This could represent an age-dependent compensatory mechanism against the well-documented mitochondrial dysfunction in this transgenic mouse model of HD (Damiano et al 2013). However, we could not detect a difference in FL-PGC-1a mRNA expression between 8-week-old wt and tg mice in the cerebellum, which is known to be a relatively resistant region to the degenerative changes in HD (Vonsattel et al 2011).…”

Mitochondrial dynamics and quality control in Huntington's disease

“…It is presently unclear whether defective complex assembly contributes for HD pathology. Indeed, whereas one study reported defective complex II assembly and activity in striatal mitochondria from mice injected with N-terminal mHtt (Damiano et al, 2013), another study reported normal assembly and activity of respiratory complexes in striatal and cortical mitochondria from R6/2 mice (Hering et al, 2015). Nevertheless, other lines of evidence suggest that the direct interaction between mHtt and neuronal mitochondria is a relevant component of HD pathology, contributing to calcium handling defects (Panov et al, 2002), disrupted mitochondrial trafficking (Orr et al, 2008) and excessive mitochondrial fission (Song et al, 2011).…”

Neuroprotective efficacy of naringin on 3-nitropropionic acid-induced mitochondrial dysfunction through the modulation of Nrf2 signaling pathway in PC12 cells

“…Both HD and 3-NP neurotoxicity are characterized by the functional impairment of mitochondrial complex II [1,7]. Disruption of mitochondrial activity is associated with the abnormal production of reactive oxidative species (ROS) like superoxide radical, hydrogen peroxide, hydroxyl radical, peroxyl radical and peroxynitrite, thereby generating oxidative stress [8].…”