Oxidative Stress: Mechanistic Insights into Inherited Mitochondrial Disorders and Parkinson's Disease

Abstract

Oxidative stress arises when cellular antioxidant defences become overwhelmed by a surplus generation of reactive oxygen species (ROS). Once this occurs, many cellular biomolecules such as DNA, lipids, and proteins become susceptible to free radical-induced oxidative damage, and this may consequently lead to cellular and ultimately tissue and organ dysfunction. Mitochondria, as well as being a source of ROS, are vulnerable to oxidative stress-induced damage with a number of key biomolecules being the target of oxidative damage by free radicals, including membrane phospholipids, respiratory chain complexes, proteins, and mitochondrial DNA (mt DNA). As a result, a deficit in cellular energy status may occur along with increased electron leakage and partial reduction of oxygen. This in turn may lead to a further increase in ROS production. Oxidative damage to certain mitochondrial biomolecules has been associated with, and implicated in the pathophysiology of a number of diseases. It is the purpose of this review to discuss the impact of such oxidative stress and subsequent damage by reviewing our current knowledge of the pathophysiology of several inherited mitochondrial disorders together with our understanding of perturbations observed in the more commonly acquired neurodegenerative disorders such as Parkinson's disease (PD). Furthermore, the potential use and feasibility of antioxidant therapies as an adjunct to lower the accumulation of damaging oxidative species and hence slow disease progression will also be discussed.

Keywords: antioxidant; mitochondria; oxidative stress; reactive oxygen species.

Figure 1

A schematic underlies the pathway of mitochondrial free radical generation and their enzymatic antioxidant defences. The mitochondrial O^•¯₂ is subsequently converted to H₂O₂ either by manganese-dependent superoxide dismutase (Mn-SOD) or copper, zinc-dependent superoxide dismutase (Cu, Zn-SOD), and then ultimately reduced to water by glutathione peroxidase (GPx).

Figure 2

A potential mechanism for the oxidative inactivation of m-aconitase by mitochondrial O^•¯₂. This oxidation reaction is accompanied by the release of a ferrous ion, which subsequently contributes to the generation of OH^• via Fenton reaction. This scenario could consequently lead to an impairment of tricarboxylic acid (TCA) cycle capacity, a deficit in mitochondrial respiratory chain (MRC) activity, and a decline in ATP production, which in turn, leads to further oxidative damage.

Figure 3

A schematic showing the role of mitochondrial dysfunction in the pathogenesis of Parkinson’s disease (PD). Neurotoxins, such as rotenone or 1-methyl-4-phenylpyridinium (MPP⁺) elicit MRC complex I deficiency, and subsequently generate reactive oxygen species (ROS), reducing levels of the antioxidant glutathione (GSH), with resulting oxidative stress. Oxidative stress induces mitochondrial permeability by transiently opening a pore, which subsequently causes depolarization of the mitochondrial membrane potential. These events ultimately lead to neural cell death via the release of pro-apoptotic mitochondrial proteins, including cytochrome c and apoptosis-initiating factor. DA: dopamine.

Figure 4

A potential mechanism of dopamine metabolism and OH^• radical formation in the striatum of PD patients as a consequence of iron accumulation and decline in GSH levels. DDC: dopa decarboxylase; 3,4 DOPAL: 3,4-dihydroxyphenylacetaldehyde.

Figure 5

A summary of oxidative stress-induced mitochondrial damage is a common mechanistic link in the pathogenesis of inherited mitochondrial disorders and PD. CL: cardiolipin; mtDNA: mitochondrial DNA.