Fight Aging!

Mitochondria are the power plants of the cell, primarily responsible for packaging adenosine triphosphate (ATP) molecules as chemical energy stores for use throughout the cell. Hundreds of mitochondria swarm inside every cell, the descendants of ancient symbiotic bacteria. These organelles retain many features characteristic of bacteria. For example, mitochondria contain a small circular genome, depleted of genes that have moved into the cell nucleus over evolutionary time. Mitochondria also constantly divide, fuse together, and swap component parts. Mitochondrial quality is controlled by the processes of mitophagy that recycle worn or damaged mitochondria, delivering them to a lysosome to be engulfed and then dismantled into raw materials.

Dysfunction of mitochondria is characteristic of aging. Cells in aged tissues exhibit changes in mitochondrial dynamics, failure of mitophagy, damage to mitochondrial DNA, increased oxidative stress as the result of changes in the way mitochondria produce ATP, and reduced ATP production. When taking place in all cells throughout a tissue, this has a profoundly harmful effect on tissue function. This is particularly true in energy-hungry tissues such as muscle and the brain. The latter is the subject of today's open access review paper, a look at what is known of the role of age-related mitochondrial dysfunction in the aging of the brain.

Mitochondrial Dysfunction: A Key Player in Brain Aging and Diseases

Despite the human brain weighing only 2% of the total body weight, almost 20% of the basal oxygen is consumed by this organ in order to produce enough energy for the approximately 86 billion neurons and 85 billion glial cells that comprise it. Glucose is the main source of energy in the adult brain and its oxidation produces ATP almost entirely through oxidative phosphorylation (OXPHOS) in the mitochondria, thus underpinning the importance of this organelle for brain homeostasis. Energy is constantly required to sustain the synthesis of neurotransmitters as well as to maintain the membrane potential needed for action potential propagation and synaptic transmission, including the re-uptake of neurotransmitters from the synaptic cleft.

A large body of evidence demonstrates that bioenergetic impairments as well as disturbances in the OXPHOS machinery of mitochondria occur in the brain during aging. Although efficient, OXPHOS produces reactive oxygen species (ROS) as a byproduct, and the brain is especially susceptible to oxidative damage because it contains a plethora of oxidizable substrates, such as fatty acids, an abundance of catalytic transition metals, and a high rate of oxygen consumption per gram of tissue. Several studies have demonstrated an association between the oxidative damage of DNA (8-OH-dG), lipids (MDA and 4-HNE), and proteins (carbonyls and protein 3-nitrotyrosine) with brain aging.

It has been proposed that the impairment of brain mitochondrial function during aging might be the result of the decreased electron transfer rate of Complex I and Complex IV. Interestingly, gene expression of mitochondrial subunits for Complexes I, III, IV, and V have been found to be down-regulated in old TG2576 mice and Ndufs4 knock-out mice, models of Alzheimer's disease pathology and of Complex I deficiency, respectively.

Importantly, the effects of neuronal oxidative stress are normally counteracted by a well-developed antioxidant system; however, during aging the antioxidant defense system may become overwhelmed. A shift to a pro-oxidized state, determined by a decrease in the GSH/GSSG ratio, with GSH serving as the body's "master" antioxidant and GSSG as the oxidized form of GSH, was found in forebrain and cerebellum from 21 month-old mice, as compared to 3 month-old controls. As the brain ages, the effects of oxidative stress on mtDNA may lead to mutations and deletions and subsequently impair the OXPHOS complexes, increase ROS production, and further exasperate oxidative stress levels. This vicious cycle may lead to decreased energy supply, increased susceptibility to apoptosis, and a progressive decline in tissue function. A 10-fold increase in mtDNA levels of 8-OHdG as well as elevated mtDNA point mutations and deletions in frontal cortex, substantia nigra, and putamen from elderly individuals above the age of 67 have been reported.

Mitochondrial quality control mechanisms, such as fusion, fission, and mitophagy, are important processes used to preserve cells against damage; however, reports indicate that as the mtDNA mutation load increases during aging these processes may begin to lose their efficiency. For example, Drp1, a protein essential for mitochondrial fission, has been shown to be down-regulated in old C57BL/6 mice, and its removal in adult mouse forebrain resulted in altered mitochondrial morphology and mitochondrial transport to the synapse, as well as decreased oxygen consumption and ATP production. Importantly, these findings suggest that mitochondrial dynamics, mitophagy, and biogenesis become impaired during aging, and may be involved in the pathogenesis of various neurodegenerative diseases.