Oxidative Stress in Neurodegenerative Diseases: From a Mitochondrial Point of View

Abstract

Age is the main risk factor for a number of human diseases, including neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, which increasing numbers of elderly individuals suffer. These pathological conditions are characterized by progressive loss of neuron cells, compromised motor or cognitive functions, and accumulation of abnormally aggregated proteins. Mitochondrial dysfunction is one of the main features of the aging process, particularly in organs requiring a high-energy source such as the heart, muscles, brain, or liver. Neurons rely almost exclusively on the mitochondria, which produce the energy required for most of the cellular processes, including synaptic plasticity and neurotransmitter synthesis. The brain is particularly vulnerable to oxidative stress and damage, because of its high oxygen consumption, low antioxidant defenses, and high content of polyunsaturated fats very prone to be oxidized. Thus, it is not surprising the importance of protecting systems, including antioxidant defenses, to maintain neuronal integrity and survival. Here, we review the role of mitochondrial oxidative stress in the aging process, with a specific focus on neurodegenerative diseases. Understanding the molecular mechanisms involving mitochondria and oxidative stress in the aging and neurodegeneration may help to identify new strategies for improving the health and extending lifespan.

Figure 1

Schematic representation of oxidative stress in health, aging, and neurodegenerative diseases. In healthy conditions, the oxidant levels mainly produced in mitochondria are kept under control due to efficient mechanisms of defense that counterbalance the excessive production of oxidants and keep the homeostasis. However during the aging, the oxidant levels increase, while the antioxidant efficiency decreases generating an imbalance that leads to a noxious condition called oxidative stress and consequently to an oxidative damage of the main biomolecules such as proteins, lipids, nucleic acids, and carbohydrates. The overall picture intensifies in neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

Figure 2

Rendition of the central role of mitochondrial deficiencies in aging. The ROS production in aged mitochondria is increased, the membrane potential appeared lower, ATP synthesis is reduced, the activity of respiratory enzyme complexes is declined, and oxidized proteins accumulate causing protein aggregation. Mitochondrial DNA (mtDNA) is also oxidized and deletions and mutations have found.

Figure 3

Schematic representation of mitochondrial dynamics. Drp1 in mitochondrial outer membrane forms chains promoting fission. The chain is stabilized by MiD49-Mff/Fis1 and MiD51-Mff/Fis1 complexes. Fusion is mediated by OPA-1 in the mitochondrial inner membrane and by Mfn1 and Mfn2 in the mitochondrial outer membrane. Drp1: dynamin-related protein-1; Fis1: mitochondrial fission protein 1; Mff: mitochondrial fission factor; MiD49: mitochondrial dynamics proteins of 49 kDa; MiD51: mitochondrial dynamic proteins of 51 kDa; OPA-1: optic atrophy 1; Mfn1: mitofusins 1; Mfn2: mitofusins 2.