The Association of VDAC with Cell Viability of PC12 Model of Huntington’s Disease

Abstract

It is becoming increasingly apparent that mitochondria dysfunction plays an important role in the pathogenesis of Huntington’s disease (HD), but the underlying mechanism is still elusive. Thus, there is a still need for further studies concerning the upstream events in the mitochondria dysfunction that could contribute to cell death observed in HD. Taking into account the fundamental role of the voltage-dependent anion-selective channel (VDAC) in mitochondria functioning, it is reasonable to consider the channel as a crucial element in HD etiology. Therefore, we applied inducible PC12 cell model of HD to determine the relationship between the effect of expression of wild type and mutant huntingtin (Htt and mHtt, respectively) on cell survival and mitochondria functioning in intact cells under conditions of undergoing cell divisions. Because after 48 h of Htt and mHtt expression differences in mitochondria functioning co-occurred with differences in the cell viability, we decided to estimate the effect of Htt and mHtt expression lasted for 48 h on VDAC functioning. Therefore, we isolated VDAC from the cells and tested the preparations by black lipid membrane system. We observed that the expression of mHtt, but not Htt, resulted in changes of the open state conductance and voltage-dependence when compared to control cells cultured in the absence of the expression. Importantly, for all the VDAC preparations, we observed a dominant quantitative content of VDAC1, and the quantitative relationships between VDAC isoforms were not changed by Htt and mHtt expression. Thus, Htt and mHtt-mediated functional changes of VDAC, being predominantly VDAC1, which occur shortly after these protein appearances in cells, may result in differences concerning mitochondria functioning and viability of cells expressing Htt and mHtt. The assumption is important for better understanding of cytotoxicity as well as cytoprotection mechanisms of potential clinical application.

Mechanism of translation control of the alternative Drosophila melanogaster Voltage Dependent Anion-selective Channel 1 mRNAs

“…VDAC1 can also regulate mitochondria-mediated apoptosis by interacting with hexokinases I and II and with proteins of the Bcl2 family, some of which are also highly expressed in many cancers 20 , 21 . Moreover, the involvement of VDAC1 in many neurodegenerative diseases, such as amyotrophic lateral sclerosis 22 , 23 , Parkinson’s 24 , Huntington’s 25 and Alzheimer’s 26 , has also been widely proven.…”

NAADP-Evoked Ca2+ Signaling Leads to Mutant Huntingtin Aggregation and Autophagy Impairment in Murine Astrocytes

“…The control group was prepared with astrocytes transfected with the plasmid pEGFP-empty (Cat #165830; Addgene, Watertown, MA, USA). As previously demonstrated in other studies, the overexpression of nonpathogenic huntingtin (Htt-Q23) does not promote protein aggregation or affect cellular viability, when compared to the mHtt-Q74 [ 53 , 54 ]. Therefore, in the present study, astrocytes transfected with the pEGFP-empty vector were used as the control group.…”

Role of Neuroglobin in the Neuroprotective Actions of Estradiol and Estrogenic Compounds

“…Indeed, estradiol promotes the expression of HTT and the formation of an HTT-neuroglobin complex and its translocation to the mitochondria [51]. In the mitochondria, HTT [77] and neuroglobin [49] interact with proteins involved in the control of apoptosis, such as VDAC. Through VDAC, neuroglobin inhibits the opening of mitochondrial permeability transition pore (mPTP) and the subsequent cytochrome c release [33].…”