Oxidative Stress and Altered Mitochondrial Function in Neurodegenerative Diseases: Lessons From Mouse Models

Abstract

Oxidative stress has been consistently linked to ageing-related neurodegenerative diseases leading to the generation of lipid peroxides, carbonyl proteins and oxidative DNA damage in tissue samples from affected brains. Studies from mouse models that express diseasespecific mutant proteins associated to the major neurodegenerative processes have underscored a critical role of mitochondria in the pathogenesis of these diseases. There is strong evidence that mitochondrial dysfunction is an early event on neurodegeneration.Mitochondria are the main cellular source of ROS and key regulators of cell death.Moreover, mitochondria are highly dynamic organelles that divide, fuse and move along axons and dendrites to supply cellular energetic demands, and therefore, impairment of any of these processes would directly impact on neuronal viability. Most of the disease-specific pathogenic mutant proteins have been shown to target mitochondria promoting oxidative stress and the mitochondrial apoptotic pathway. In addition, disease-specific mutant proteins may also impair mitochondrial dynamics and recycling of damaged mitochondria via autophagy. Thus, all these data suggest that ROS-mediated defective mitochondria may accumulate during and contribute to disease progression, indicating that strategies aimed to improve mitochondrial function or ROS scavenging may be of potential clinical relevance.

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…Therefore, if ROS are not efficiently eliminated by the cellular antioxidants the cellular components become damaged by oxidation, which in turn leads to further oxidative stress, cellular dysfunction and even cell death (for a review in cellular antioxidants, repair of oxidative damage and their implication in neurodegeneration see Gros et al, 2002;Ahsan et al, 2009;Fernandez-Checa et al, 2010).…”

The Cross-Talk Between Mitochondria and the Nucleus in the Response to Oxidative Stress Associated with Mitochondrial Dysfunction in Mitochondrial Encephalomyopathies

“…Since mitochondria are responsible for the supply of the majority of ATP in human cells via respiration and OXPHOS, the defective mitochondria in affected tissue cells cause not only inefficient ATP production but also increased production of ROS. The symptoms of mitochondrial encephalomyopathies and neuromuscular disorders caused by mitochondrial dysfunction-elicited oxidative stress have been proven to be similar to those documented in the patients with mitochondrial diseases (Fernández-Checa et al, 2010). Oxidative stress elicited by mitochondrial dysfunction can further increase oxidative damage to various biomolecules in mitochondria.…”

Role of Astrocytes in Neurodegenerative Diseases

“…Morphologically, HO-1 is expressed in shaped-like astrocytes, and does not seem to be expressed by neurons. Scale bar, 50 µm www.intechopen.com Imuta et al, 2007;Ku et al, 2006;Le et al, 1999;Takeda et al, 2000), its overproduction in astrocytes may contribute to iron overload and mitochondrial insufficiency, characteristic of some neurodegenerative disorders (Fernandez-Checa et al, 2010;Serviddio et al, 2011). HO-1 is expressed by approximately 86% (Schipper et al, 1995) and 77.1% (Schipper et al, 1998) of GFAP-positive astrocytes in AD and PD, respectively, suggesting a possible role in the pathogenesis of these neurodegenerative diseases.…”