'Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich’s ataxia'

Abstract

Friedreich's ataxia (FRDA) is an inherited neurodegenerative disease. The mutation consists of a GAA repeat expansion within the FXN gene, which downregulates frataxin, leading to abnormal mitochondrial iron accumulation, which may in turn cause changes in mitochondrial function. Although, many studies of FRDA patients and mouse models have been conducted in the past two decades, the role of frataxin in mitochondrial pathophysiology remains elusive. Are the mitochondrial abnormalities only a side effect of the increased accumulation of reactive iron, generating oxidative stress? Or does the progressive lack of iron-sulphur clusters (ISCs), induced by reduced frataxin, cause an inhibition of the electron transport chain complexes (CI, II and III) leading to reactive oxygen species escaping from oxidative phosphorylation reactions? To answer these crucial questions, we have characterised the mitochondrial pathophysiology of a group of disease-relevant and readily accessible neurons, cerebellar granule cells, from a validated FRDA mouse model. By using live cell imaging and biochemical techniques we were able to demonstrate that mitochondria are deregulated in neurons from the YG8R FRDA mouse model, causing a decrease in mitochondrial membrane potential (▵Ψm) due to an inhibition of Complex I, which is partially compensated by an overactivation of Complex II. This complex activity imbalance leads to ROS generation in both mitochondrial matrix and cytosol, which results in glutathione depletion and increased lipid peroxidation. Preventing this increase in lipid peroxidation, in neurons, protects against in cell death. This work describes the pathophysiological properties of the mitochondria in neurons from a FRDA mouse model and shows that lipid peroxidation could be an important target for novel therapeutic strategies in FRDA, which still lacks a cure.

Mitochondrial dysfunction in neurodegenerative diseases and the potential countermeasure

“…FRDA's GAA expansion mutation leads to deficiency of the frataxin protein, causing mitochondrial dysfunction through promoting ROS production . Recently, studies by Abeti et al revealed that FRDA mouse models show a decrease in mitochondrial membrane potential that is caused by an activity imbalance between Complex I and II in the electron transport chain. This imbalance causes ROS generation in the mitochondrial intermembrane space and the matrix, and the subsequent lipid peroxidation results in neuron degeneration.…”

The role of oxidative stress in Friedreich's ataxia

“…Characterization of the YG8 and YG8sR models, carrying FXN exogenous genes with 90 + 190 or 200 GAA repeats, respectively, showed age‐dependent FRDA symptoms such as ambulatory difficulties, decreased frataxin mRNA levels, abnormal root ganglia, reduced aconitase activity and oxidative stress . Neurons derived from the YG8 mouse also showed a reduction in Complex I activity, increased oxidative stress in both mitochondria and cytosol, and lipid peroxidation . These models, in addition to recapitulating the characteristic FRDA phenotype, were also suitable for studying the genetic aspects of the disease, such as GAA repeat instability , gene silencing induced by the expansion and novel gene therapy approaches .…”

Enzymatic and free radical formation of cis- and trans- epoxyeicosatrienoic acids in vitro and in vivo

“…Detailed mechanism of peroxyl radical addition reactions has been discussed by Xu et al [2]. Lipid peroxidation in vivo has been linked to the underlying pathophysiology of various disease states, including atherosclerosis, myocardial ischemia-reperfusion injury, diabetes, cancer, and neurodegenerative injury [3-7]. …”