Brain mitochondrial dysfunction in aging, neurodegeneration, and Parkinson's disease

Abstract

Brain senescence and neurodegeneration occur with a mitochondrial dysfunction characterized by impaired electron transfer and by oxidative damage. Brain mitochondria of old animals show decreased rates of electron transfer in complexes I and IV, decreased membrane potential, increased content of the oxidation products of phospholipids and proteins and increased size and fragility. This impairment, with complex I inactivation and oxidative damage, is named "complex I syndrome" and is recognized as characteristic of mammalian brain aging and of neurodegenerative diseases. Mitochondrial dysfunction is more marked in brain areas as rat hippocampus and frontal cortex, in human cortex in Parkinson's disease and dementia with Lewy bodies, and in substantia nigra in Parkinson's disease. The molecular mechanisms involved in complex I inactivation include the synergistic inactivations produced by ONOO- mediated reactions, by reactions with free radical intermediates of lipid peroxidation and by amine-aldehyde adduction reactions. The accumulation of oxidation products prompts the idea of antioxidant therapies. High doses of vitamin E produce a significant protection of complex I activity and mitochondrial function in rats and mice, and with improvement of neurological functions and increased median life span in mice. Mitochondria-targeted antioxidants, as the Skulachev cations covalently attached to vitamin E, ubiquinone and PBN and the SS tetrapeptides, are negatively charged and accumulate in mitochondria where they exert their antioxidant effects. Activation of the cellular mechanisms that regulate mitochondrial biogenesis is another potential therapeutic strategy, since the process generates organelles devoid of oxidation products and with full enzymatic activity and capacity for ATP production.

Keywords: antioxidant therapy; complex I syndrome; mitochondria-targeted antioxidants; vitamin E.

Figure 1

Statistical correlations involving: (A) mitochondrial enzyme activities (complexes I and IV and mtNOS) and mitochondrial oxidative damage (r² = 0. 84; p < 0.01 for complexes I and IV; r² = 0.90; p < 0.01 for mtNOS); (B) enzyme activities and neurological tests (tightrope, r² = 0.62; p < 0.001; T-maze, r² = 0.56; p < 0.05) and enzyme activities and median (r² = 0.46; p < 0.05), and maximal (r² = 0.31; p < 0.01), life spans (C) in male mice. Data from (Navarro et al., 2002, 2004, 2005a, 2007). For the neurological assays, individual mice were subjected every 2 weeks to the tightrope and the T-maze tests (Navarro et al., 2002). For the tightrope test, mice were placed hanging from their anterior legs in the middle of a 60-cm tightrope and the test was considered successful when mice reached the column at the end of the rope in less of 30 s. For the T-maze test, mice were challenged in a T-shaped maze of 50 cm arms and the test was considered successful when mice moved toward the T-intersection in less than 30 s. Modified from Boveris and Navarro (2008a,b).

Figure 2

Scheme illustrating the hypothesis of the time course of the levels of mitochondrial oxidation and nitration products, associated with mitochondrial turnover for brain mitochondria as a function of time and age. AU, arbitrary units. Modified from Navarro and Boveris (2008).