Mitochondria in Amyotrophic Lateral Sclerosis: A Trigger and a Target

Abstract

Strong evidence shows that mitochondrial dysfunction is involved in amyotrophic lateral sclerosis (ALS), but despite the fact that mitochondria play a central role in excitotoxicity, oxidative stress and apoptosis, the intimate underlying mechanism linking mitochondrial defects to motor neuron degeneration in ALS still remains elusive. Morphological and functional abnormalities occur in mitochondria in ALS patients and related animal models, although their exact nature and extent are controversial. Recent studies postulate that the mislocalization in mitochondria of mutant forms of copper-zinc superoxide dismutase (SOD1), the only well-documented cause of familial ALS, may account for the toxic gain of function of the enzyme, and hence induce motor neuron death. On the other hand, mitochondrial dysfunction in ALS does not seem to be restricted only to motor neurons as it is also present in other tissues, particularly the skeletal muscle. The presence of this ‘systemic’ defect in energy metabolism associated with the disease is supported in skeletal muscle tissue by impaired mitochondrial respiration and overexpression of uncoupling protein 3. In addition, the lifespan of transgenic mutant SOD1 mice is increased by a highly energetic diet compensating both the metabolic defect and the motorneuronal function. In this review, we will focus on the mitochondrial dysfunction linked to ALS and the cause-and-effect relationships between mitochondria and the pathological mechanisms thought to be involved in the disease.

Zinc Regulates the Stability of Repetitive Minisatellite DNA Tracts During Stationary Phase

“…Low zinc intake can lead to a dramatic loss in immune defense capacity (Fernandes et al 1979) through apoptosis of precursor T-and B-cells, which results in lymphopenia (Fraker 2005). Zinc levels have been linked to cancer, particularly cancer of the prostate (Dhar et al 1973;Franklin 1998, 2000;Platz and Helzlsouer 2001;Bataineh et al 2002;Ho 2004), and to neurodegenerative disease, including amyotrophic lateral sclerosis (Dupuis et al 2004;Ho 2004). Lesser effects include airway inflammation and asthma (Murgia et al 2006) and potentially depression (Nowak et al 2005).…”

Oxidative stress biomarkers in sporadic ALS

“…In fact, a recent series of studies suggest the possibility of systemic involvement in sALS [27]. In ALS patients, cultured monocytes have increased inflammatory cytokine production [28], cutaneous collagen fibers are abnormal [29], systemic glutamate metabolism is impaired [30], the antioxidative defense system of erythrocytes is reduced [31], patients are in a hypermetabolic state due to abnormal skeletal muscle metabolism [32], and muscle mitochondria are not only structurally abnormal [33,34], but have primary abnormalities known to cause an ALS-like syndrome [35]. A major source of 'systemic' oxidative stress is clearly generated in skeletal muscle, which constitutes 40 to 45% of body mass [36].…”

Mitochondrial Dysfunction in SOD1G93A-Bearing Astrocytes Promotes Motor Neuron Degeneration: Prevention by Mitochondrial-Targeted Antioxidants

“…Mitochondrial dysfunction and oxidative stress have been involved in amyotrophic lateral sclerosis (ALS) pathogenesis [for review, see Dupuis et al (2004), Bruijn et al (2004), and Manfredi and Xu (2005)]. Previous reports described decreased mitochondrial respiratory activity in spinal cords from transgenic (Tg) superoxide dismutase-1 (SOD1) G93A mice Mattiazzi et al, 2002) and in cellular models of the disease (Menzies et al, 2002).…”