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.

Figure 1

OXPHOS–oxidative stress–neurodegeneration connections. OXPHOS activity produces ROS, which could induce mutations in the mtDNA. In turn, mtDNA mutations can lead to the inhibition of OXPHOS, which can increase the production of ROS. The ‘vicious cycle’ theory of aging suggests that an exponential increase in ROS production and oxidative damage mediated by these interactions could be a strong contributor to age-associated neurodegenerative diseases. However, in vivo evidence for a causative relationship between these players has not been provided. Defects in OXPHOS can contribute to aging in an oxidative stress-independent manner, and the latter could be a marker of senescence. In addition, misfolded proteins, such as Aβ, were also shown to impair OXPHOS and possibly other metabolic systems.