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.

Compromised MAPK signaling in human diseases: an update

“…PINK1, Parkin, and HtrA2 function in mitochondrial biogenesis and the autophagic degradation of mitochondria (mitophagy) (Desideri and Martins 2012). In ALS, SOD1 mutants induce mitochondrial dysregulation including disturbance of mitochondrial Ca 2+ flow (Tan et al 2014). The C9orf72 gene has been identified as the most frequently mutated gene in the familial forms of ALS and frontotemporal dementia (Mendez and Sattler 2014).…”

“…SOD1, the first identified ALS gene, has been extensively studied with regard to its role in the pathogenesis of this condition with the use of transgenic mice expressing various ALS-linked mutants of human SOD1 (Vinsant et al 2013). Such studies have revealed various mitochondrial abnormalities in these mice, including impairment of ATP permeation through the mitochondrial outer membrane, membrane hyperpolarization, and disturbance of mitochondrial Ca 2+ flow, which is functionally connected to Ca 2+ signaling in the endoplasmic reticulum (Tadic et al 2014;Tan et al 2014) (Fig. 2j).…”

Altered Metabolic Homeostasis in Amyotrophic Lateral Sclerosis: Mechanisms of Energy Imbalance and Contribution to Disease Progression

“…Such observations have led to the hypothesis that mitochondrial dysfunction plays an important role in the pathogenesis of ALS, and a large number of studies in ALS patients and animal models have found mitochondrial abnormalities in neuronal and non-neuronal tissues [reviewed in [142]]. Furthermore, animal studies have revealed mitochondrial dysfunction in the pre-symptomatic and early phases of disease [143,144,145,146,147], implying that mitochondrial dysfunction is an early event that triggers disease rather than the end product of neuronal cell degeneration. Critically, mitochondrial dysfunction leads to the accumulation of oxygen free radicals and reduced ATP production from oxidative phosphorylation, reducing cell function and energy availability and leading to cell death [148,149].…”

Canine degenerative myelopathy: a model of human amyotrophic lateral sclerosis

“…Notably, in mutant SOD1-linked ALS functional defects in mitochondria can be observed early on, before symptoms are manifest (Tan et al, 2014). Several mechanisms, such as disruption of energy metabolism, impaired protein import machinery, and impaired calcium buffering, may contribute to mutant SOD1-mediated damage to mitochondria (Rothstein, 2009).…”