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Aging is characterized by increasing dysfunction in mitochondria, the power plants of the cell, responsible for packaging chemical energy store molecules, ATP, to power cellular operations. Mitochondrial decline in aging is most studied in energy hungry tissues such as the muscles and brain, and it is widely accepted that mitochondrial dysfunction is an important feature of neurodegenerative diseases. Mitochondrial dysfunction is likely caused by damage to mitochondrial DNA and loss of quality control mechanisms responsible for destroying malfunctioning mitochondria. It manifests as a reduced supply of ATP and increased generation of oxidative molecules.
Oxidative reactions that disrupt cellular machinery occur constantly even in youth, and cells possess many antioxidant and repair mechanisms to keep this damage under control. Oxidative damage is even used as necessary signaling in processes such as the beneficial response to exercise. Consistently raised amounts of oxidative molecules are harmful in many ways, however, not just damaging internal cellular operations, but also producing downstream issues such as altered forms of cholesterol that contribute to the progression of atherosclerosis.
Aging is the primary risk factor for a number of human diseases, as well as neurodegenerative disorders. A growing body of evidence highlights bioenergetic impairments as well as alterations in the reduction-oxidation (redox) homeostasis in the brain with the increasing of the age. The brain is composed by highly differentiated cells that populate different anatomical regions and requires about 20% of body basal oxygen for its functions. Thus, it is not surprising that alterations in brain energy metabolisms lead to neurodegeneration.
Cellular energy is mainly produced via oxidative phosphorylation taking place within mitochondria, which are crucial organelles for numerous cellular processes, such as energy metabolism, calcium homeostasis, lipid biosynthesis, and apoptosis. Glucose oxidation is the most relevant source of energy in the brain, because of its high rate of ATP generation needed to maintain neuronal energy demands. Thus, neurons rely almost exclusively on the mitochondria, which produce the energy required for most of the cellular processes, including synaptic plasticity and neurotransmitter synthesis.
Reactive oxygen species (ROS) are normally produced in the cell of living organisms as a result of normal cellular metabolism and are fundamental in the maintenance of cellular homeostasis. When an imbalance between ROS production and detoxification occurs, ROS production may overwhelm antioxidant defenses, leading to the generation of a noxious condition called oxidative stress and overall to the impairment of the cellular functions. This phenomenon is observed in many pathological cases involving mitochondrial dysfunction, as well as in aging. The brain is particularly vulnerable to oxidative stress and damage, because of its high oxygen consumption, low antioxidants defenses, and high content of polyunsaturated fats very prone to be oxidized.
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. Although a large amount of data support the role of mitochondrial ROS production in aging, it has also recently been demonstrated the involvement of the mitochondrial permeability transition in the mechanisms of aging. The age-associated decrease in mitochondrial membrane potential correlated with reduced ATP synthesis in tissues of old animals. The mitochondrial permeability transition is due to a nonspecific pore called the mitochondrial permeability transition pore (mPTP) occurring when mitochondria become overloaded with calcium. Indeed, it is well known that aging alters cytosolic calcium pick-up and the sensitivity of the mPTP to calcium enhanced under oxidative stress conditions.
Neurons are postmitotic highly differentiated cells with a lifespan similar to that of the whole organism. These excitable cells are more sensitive to the accumulation of oxidative damages compared to dividing cells and are more prone to accumulating defective mitochondria during aging. Thus, it is not surprising the importance of protecting systems, including antioxidant defenses, to maintain neuronal integrity and survival. All the neurodegenerative disorders share several common features, such as the accumulation of abnormally aggregated proteins and the involvement of oxidative damage and mitochondrial dysfunction. Many of the genes associated with Parkinson’s disease or ALS are linked to mitochondria. In addition, all aggregated misfolded proteins (β-amyloid, tau, and α-synuclein) are known to inhibit mitochondrial function and induce oxidative stress. Therefore, the identification of common mechanisms underlying neurodegenerative diseases, including mitochondrial dysfunction, will increase our understanding of the essential requirements for neuronal survival that can inform future neuroprotective therapies.