Calcium Deregulation: Novel Insights to Understand Friedreich's Ataxia Pathophysiology.

Marta Maiolino,Paola Giunti,Rosella Abeti,Alexander F Brown,Sandip Patel

doi:10.3389/fncel.2018.00264

Marta Maiolino, Paola Giunti + Show 3 more

Open Access

https://doi.org/10.3389/fncel.2018.00264

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Abstract

Friedreich’s Ataxia (FRDA) is a neurodegenerative disorder, characterized by degeneration of dorsal root ganglia, cerebellum and cardiomyopathy. Heart failure is one of the most common causes of death for FRDA patients. Deficiency of frataxin, a small mitochondrial protein, is responsible for all clinical and morphological manifestations of FRDA. The focus of our study was to investigate the unexplored Ca2+ homeostasis in cerebellar granule neurons (CGNs) and in cardiomyocytes of FRDA cellular models to understand the pathogenesis of degeneration. Ca2+ homeostasis in neurons and cardiomyocytes is not only crucial for the cellular wellbeing but more importantly to generate action potential in both neurons and cardiomyocytes. By challenging Ca2+ homeostasis in CGNs, and in adult and neonatal cardiomyocytes of FRDA models, we have assessed the impact of frataxin decrease on both neuronal and cardiac physiopathology. Interestingly, we have found that Ca2+ homeostasis is altered both cell types. CGNs showed a Ca2+ mishandling under depolarizing conditions and this was also reflected in the endoplasmic reticulum (ER) content. In cardiomyocytes we found that the sarcoplasmic reticulum (SR) Ca2+ content was pathologically reduced, and that mitochondrial Ca2+ uptake was impaired. This phenomenon is due to the excess of oxidative stress under FRDA like conditions and the consequent aberrant modulation of key players at the SR/ER and mitochondrial level that usually restore the Ca2+ homeostasis. Our findings demonstrate that in both neurons and cardiomyocytes the decreased Ca2+ level within the stores has a comparable detrimental impact in their physiology. In cardiomyocytes, we found that ryanodine receptors (RyRs) may be leaking and expel more Ca2+ out from the SR. At the same time mitochondrial uptake was altered and we found that Vitamin E can restore this defect. Moreover, Vitamin E protects from cell death induced by hypoxia-reperfusion injury, revealing novel properties of Vitamin E as potential therapeutic tool for FRDA cardiomyopathy.

Highlights

Friedreich’s ataxia is caused by frataxin insufficiency leading to changes in iron metabolism that inhibits mitochondrial respiration and promotes reactive oxygen species (ROS) generation, causing mitochondrial dysfunction, oxidative stress and subsequent mitochondrial iron accumulation (Oudit et al, 2006)
The efficiency of the frataxin knock down (FxnKD) was assessed via immunocytochemistry and we found that the level of frataxin was significantly reduced when compared to control cells (Supplementary Figures S1A–D)
These results demonstrate that by reducing the level of frataxin expression there is an overall increase of ROS both in the cytosol and the mitochondria

Summary

Introduction

Friedreich’s ataxia is caused by frataxin insufficiency leading to changes in iron metabolism that inhibits mitochondrial respiration and promotes reactive oxygen species (ROS) generation, causing mitochondrial dysfunction, oxidative stress and subsequent mitochondrial iron accumulation (Oudit et al, 2006). These effects result in selected neuronal atrophy, where the primary sites of pathology are the dorsal root ganglia (DRG) (Dyck et al, 1968), and a characteristic proliferation of the synaptic terminals in the dentate nucleus of the cerebellum (Koeppen et al, 2007). We have investigated whether oxidative stress can be linked to Ca2+ mishandling in CGNs

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