The mitochondrial impairment, oxidative stress and neurodegeneration connection: reality or just an attractive hypothesis?

Abstract

Aging is the most important risk factor for common neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Aging in the central nervous system has been associated with elevated mutation load in mitochondrial DNA, defects in mitochondrial respiration and increased oxidative damage. These observations support a 'vicious cycle' theory which states that there is a feedback mechanism connecting these events in aging and age-associated neurodegeneration. Despite being an extremely attractive hypothesis, the bulk of the evidence supporting the mitochondrial vicious cycle model comes from pharmacological experiments in which the modes of mitochondrial enzyme inhibition are far from those observed in real life. Furthermore, recent in vivo evidence does not support this model. In this review, we focus on the relationship among the components of the putative vicious cycle, with particular emphasis on the role of mitochondrial defects on oxidative stress. Mitochondrial respiratory chain and reactive oxygen species productionMitochondria, being the key players in ATP production and diverse cell signaling events, are essential organelles for the survival of eukaryotic cells. Unlike all other organelles in animals, the mitochondria have their own genome (mitochondrial DNA; mtDNA) that encodes components of the oxidative phosphorylation (OXPHOS) system. The mitochondrial OXPHOS machinery is composed of five multisubunit complexes (complex I-V). From Krebs cycle intermediates (NADH and FADH 2 ), electrons feed into complex I or II, and are transferred to complex III, then to complex IV, and finally to O 2 . The redox energy released during the electron transfer process in complexes I, III and IV is utilized to actively pump out H + from the mitochondrial matrix to the intermembrane space, generating the electrochemical gradient of H + across the inner membrane which is ultimately utilized by complex V to produce ATP [1].This elegant system for energy production, however, is not perfect. A small portion (up to 2%) of electrons passing through the electron transport chain, mostly at complex I and complex III, react with molecular oxygen and yield superoxide anion, which can be converted into other reactive oxygen species (ROS) such as hydrogen peroxide and the highly reactive hydroxyl radical through enzymatic and nonenzymatic reactions [2]. Cells are endowed with robust endogenous antioxidant systems to counteract excessive ROS. It is believed that ROS, in particular hydrogen peroxide, have physiological roles as signaling molecules [3,4]. However,

Taking a “good” look at free radicals in the aging process

“…The description of these results and their impact on the validity and the future of the theory is the main subject of recent reviews in the field [22][23][24][25].…”

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…Nevertheless, if mitochondrial dysfunction is the cause or effect of protein aggregation in PD is still controversial. Some studies showed that complex I inhibition with drugs like rotenone promoted a number of PD symptoms, such as degeneration of substantia nigra neurons, increased ROS and α-synuclein aggregates (reviewed in Fukui andMoraes, 2008 andAndersen, 2011). In addition, the increased α-synuclein oligomerization in PD cybrids through a complex I-mediated mechanism that involves the cystoskeleton disorganization, supported the hypothesis of a mitochondrial dysfunction-induced PD (Esteves et al, 2009).…”

The new FDG brain revolution: the neurovascular unit and the default network

“…Indeed, the role of functional imaging with FDG PET would not be so important if the results of two decades of investigation into the molecular genetics and pathophysiology of brain disorders had not clearly demonstrated that degeneration occurs preferentially at the synaptic level and involves dysfunction in mitochondrial energy metabolism [31][32][33]. For this reason, this technique is nowadays considered the most appropriate approach to track local energetic transformation in the living human brain [34].…”