Role of mitochondria in mutant SOD1 linked amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an adult onset characterized by loss of both upper and lower motor neurons. In ~10% of cases, patients developed ALS with an apparent genetic linkage (familial ALS or fALS). Approximately 20% of fALS displays mutations in the SOD1 gene encoding superoxide dismutase 1. There are many proposed cellular and molecular mechanisms among which, mitochondrial dysfunctions occur early, prior to symptoms occurrence. In this review, we modeled the effect of mutant SOD1 protein via the formation of a toxic complex with Bcl2 on mitochondrial bioenergetics. Furthermore, we discuss that the shutdown of ATP permeation through mitochondrial outer membrane could lead to both respiration inhibition and temporary mitochondrial hyperpolarization. Moreover, we reviewed mitochondrial calcium signaling, oxidative stress, fission and fusion, autophagy and apoptosis in mutant SOD1-linked ALS. Functional defects in mitochondria appear early before symptoms are manifested in ALS. Therefore, mitochondrial dysfunction is a promising therapeutic target in ALS.

Keywords: Amyotrophic lateral sclerosis; Mitochondria; Oxidative stress.

Figure 1

Kinetic model of generation of proton gradient (Not drawn to scale). ADP permeates through VDAC channels in the outer membrane, translocates through ANT in the inner membrane, where it is phosphorylated into ATP inside the matrix by ATP synthase through dissipation of proton gradient, with apparent kinetic constant of k2. The proton gradient is generated through respiratory complexes with apparent kinetic constant of k1 and subjected to the leakage through the inner membrane.

Figure 2

Summarized impact of mutant SOD1/Bcl2 on mitochondria. Mutant SOD1 binds to Bcl2, expose its BH3 domain, alters VDAC conducting states, resulting in reduced ATP production, enhanced calcium signaling, increased mitochondrial potential and ROS production. We also propose that Quinone from Complex I is trapped in the oxidized form.