The Link between Oxidative Stress, Redox Status, Bioenergetics and Mitochondria in the Pathophysiology of ALS

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease of the motor system. It is characterized by the degeneration of both upper and lower motor neurons, which leads to muscle weakness and paralysis. ALS is incurable and has a bleak prognosis, with median survival of 3–5 years after the initial symptomatology. In ALS, motor neurons gradually degenerate and die. Many features of mitochondrial dysfunction are manifested in neurodegenerative diseases, including ALS. Mitochondria have shown to be an early target in ALS pathophysiology and contribute to disease progression. Disruption of their axonal transport, excessive generation of reactive oxygen species, disruption of the mitochondrial structure, dynamics, mitophagy, energy production, calcium buffering and apoptotic triggering have all been directly involved in disease pathogenesis and extensively reported in ALS patients and animal model systems. Alterations in energy production by motor neurons, which severely limit their survival capacity, are tightly linked to the redox status and mitochondria. The present review focuses on this link. Placing oxidative stress as a main pathophysiological mechanism, the molecular interactions and metabolic flows involved are analyzed. This leads to discussing potential therapeutic approaches targeting mitochondrial biology to slow disease progression.

NAD+ Precursors and Antioxidants for the Treatment of Amyotrophic Lateral Sclerosis

“…Consequently, this background strongly supports the notion of a close relationship between oxidative stress, NAD + levels, cellular redox status, and mitochondrial function, all of which are involved in the pathophysiology of ALS [8].…”

“…NAD + is a coenzyme in redox reactions, a donor of ADP-ribose for ADP-ribosylation reactions, a precursor of cyclic ADP-ribose, and a substrate for sirtuins (SIRTs) that use the cofactor to remove acetyl groups from proteins. SIRTs link NAD + levels to mitochondrial function, dynamics and biogenesis, and to cellular antioxidant defenses [8,22]. Interestingly, under the conditions of reduced cellular energy (as it occurs in the MNs during the progression of ALS), SIRTs may not consume sufficient NAD + to preclude any cell survival-promoting effects of its deacetylase action on protein substrates [23].…”

“…Biomedicines 2021, 9, 1000 2 of 13 There is mounting evidence involving oxidative stress as a main pathophysiological mechanism leading to MN damage and death [8]. Conceptually, oxidative stress is an imbalance of oxygen-derived free radicals and antioxidants in the body, which can lead to cell and organ damage [9].…”

“…Oxidative stress and alterations in redox status, bioenergetics, and NAD + metabolism are clearly linked to the pathophysiology of ALS [8]. Thus, the aim of this review is to discuss the possibility of using both NAD + promoters and antioxidants as complementary therapies to slow down the progression of MN damage.…”

Biomolecular Modifications Linked to Oxidative Stress in Amyotrophic Lateral Sclerosis: Determining Promising Biomarkers Related to Oxidative Stress

“…Mitochondria, which are the heart of redox reactions and generate ROS species, play essential roles in the survival of various cells, including motor neurons [47]. Mitochondrial DNA is more exposed to ROS than nuclear DNA because mitochondrial DNA exists in the proximity of the inner mitochondrial membrane in which ROS is formed, lacks protective histones, and has less efficient repair [48].…”