Mitochondrial alterations accompanied by oxidative stress conditions in skin fibroblasts of Huntington\u2019s disease patients

Paulina Jędrak,Paweł Mozolewski,Mariusz R Więckowski,Grzegorz Węgrzyn

doi:10.1007/s11011-018-0308-1

Abstract

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder manifesting as progressive impairment of motor function and different neuropsychiatric symptoms caused by an expansion of CAG repeats in huntingtin gene (HTT). Mitochondrial dysfunction and bioenergetic defects can contribute to the course of the disease, however, the molecular mechanism underlying this process is still largely unknown. In this study, we aimed to determine several mitochondrial parameters in HD fibroblasts and assess their relevance to the disease progression as well as to value mitochondrial pathology in peripheral cells as disease potential biomarker. We showed that HD fibroblasts demonstrate significantly lower growth rate compared to control fibroblasts despite the lack of cell cycle perturbations. In order to investigate mitochondrial contribution to cell growth differences between HD and healthy cells, we provided insight into various mitochondrial parameters. Conducted experiments have revealed a significant reduction of the ATP level in HD fibroblasts accompanied by a decrease in mitochondrial metabolic activity in relation to the cells from healthy donors. Importantly, there were no differences in the mitochondrial membrane potential (mtΔΨ) and OXPHOS complexes’ levels. Slightly increased level of mitochondrial superoxide (mt. O2•-), but not cytosolic reactive oxygen species (cyt. ROS), has been demonstrated. We have also observed significantly elevated levels of some antioxidant enzymes (SOD2 and GR) which may serve as an indicator of antioxidant defense system in HD patients. Thus, we suggest that mitochondrial alterations in skin fibroblasts of Huntington’s disease patients might be helpful in searching for novel disease biomarkers.

Highlights

Huntington disease (HD) is an autosomal dominant, neurodegenerative disease caused by a CAG repeat extension in the huntingtin gene (HTT) gene, encoding the huntingtin protein (Htt), which resultsGrzegorz Węgrzyn and Mariusz R
It has been demonstrated previously that HD fibroblasts manifest some of the mitochondrial dysfunction consistent with the neuronal disease phenotype (Sassone et al 2009; Petersen et al 2014; Marchina et al 2014; Jędrak et al 2017)
We investigated whether the mitochondrial alterations that could be observed in fibroblasts from patients with HD correlate with the disease severity and may serve as a potential biomarker of HD

Summary

Introduction

Huntington disease (HD) is an autosomal dominant, neurodegenerative disease caused by a CAG repeat extension in the HTT gene, encoding the huntingtin protein (Htt), which resultsGrzegorz Węgrzyn and Mariusz R. Huntington disease (HD) is an autosomal dominant, neurodegenerative disease caused by a CAG repeat extension in the HTT gene, encoding the huntingtin protein (Htt), which results. Conformational changes in the mutant huntingtin (mHtt) cause accumulation of the protein in the cytoplasm and the nucleus of neurons. This event is probably responsible for degradation of neurons, it is still under debate what is the exact mechanism underlying the cell loss. No therapy is currently available to reverse the symptoms or delay the onset of HD, and the disease is fatal within 15–20 years after diagnosis (Gusella et al 1983; The Huntington’s Disease Collaborative Research Group 1993; Roos 2010)

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