Distinction of sporadic and familial forms of ALS based on mitochondrial characteristics

Abstract

Bioenergetic failure, oxidative stress, and changes in mitochondrial morphology are common pathologic hallmarks of amyotrophic lateral sclerosis (ALS) in several cellular and animal models. Disturbed mitochondrial physiology has serious consequences for proper functioning of the cell, leading to the chronic mitochondrial stress. Mitochondria, being in the center of cellular metabolism, play a pivotal role in adaptation to stress conditions. We found that mitochondrial dysfunction and adaptation processes differ in primary fibroblasts derived from patients diagnosed with either sporadic or familial forms of ALS. The evaluation of mitochondrial parameters such as the mitochondrial membrane potential, the oxygen consumption rate, the activity and levels of respiratory chain complexes, and the levels of ATP, reactive oxygen species, and Ca2+ show that the bioenergetic properties of mitochondria are different in sporadic ALS, familial ALS, and control groups. Comparative statistical analysis of the data set (with use of principal component analysis and support vector machine) identifies and distinguishes 3 separate groups despite the small number of investigated cell lines and high variability in measured parameters. These findings could be a first step in development of a new tool for predicting sporadic and familial forms of ALS and could contribute to knowledge of its pathophysiology.—Walczak, J., Dębska‐Vielhaber, G., Vielhaber, S., Szymański, J., Charzyńska, A., Duszyński, J., Szczepanowska, J. Distinction of sporadic and familial forms of ALS based on mitochondrial characteristics. FASEB J. 33, 4388–4403 (2019). http://www.fasebj.org

Protocatechuic Acid Extends Survival, Improves Motor Function, Diminishes Gliosis, and Sustains Neuromuscular Junctions in the hSOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis

“…Oxidative stress markers such as glutathione peroxidase, malondialdehyde, glutathione status, and 8-oxodeoxyguanosine demonstrate significant alterations in ALS patients [20,21]. Furthermore, mitochondrial dysfunction and mutations in genes that affect mitochondrial processes have been linked to ALS [22][23][24][25][26]. Specifically, in the case of ALS caused by mutations in SOD1, the mutant SOD1 protein has been shown to aggregate within mitochondria, resulting in mitochondrial dysfunction and mitochondrial oxidative stress [24,27].…”

ASCs-Exosomes Recover Coupling Efficiency and Mitochondrial Membrane Potential in an in vitro Model of ALS

“…In ALS patient’s lymphocytes, enzymatic assays on NADH-ferricyanide reductase showed a reduction of complex I activity compared to controls (Ghiasi et al, 2012). In patient fibroblasts, the evaluation of mitochondrial function revealed a specific deficit in ALS patients compared to control groups (Walczak et al, 2019). In isolated coupled mitochondria obtained from SOD1(G93A) mice tissues (brain, liver, and spinal cord) at disease onset, a reduced complex I-linked phosphorylative activity (sustained by glutamate and malate) was reported (Mattiazzi et al, 2002).…”

Pyruvate Dehydrogenase and Tricarboxylic Acid Cycle Enzymes Are Sensitive Targets of Traumatic Brain Injury Induced Metabolic Derangement

“…Dysfunctional mitochondria with reduced oxidative phosphorylating capacities (due to the imbalance in the stoichiometric ratio formed by moles of transferred electrons through ETC:moles of protons pumped by complexes I, III, and IV:moles of oxygen reduced to water:moles of ATP produced by complex V) are a common feature of chronic neurodegenerations. Alzheimer’s disease [6], Parkinson’s disease [7], multiple sclerosis [8], and amyotrophic lateral sclerosis [9] are characterized by an energy deficit causing an increase in apoptosis, as well as oxidative/nitrosative stress due to the excess production of reactive oxygen (ROS) and nitrogen species (RNS). All these phenomena are strictly connected to mitochondrial malfunctioning [10].…”