Every cell contains hundreds of mitochondria, the distant descendants of ancient symbiotic bacteria that still contain a remnant circular genome, the mitochondrial DNA. The most important task undertaken by mitochondria is the production of the chemical energy store molecule adenosine triphosphate (ATP). A constant supply of ATP is needed to power the functions of the cell, and mitochondria are thus essential to cell function. Mitochondrial dysfunction is a feature of aging, arising in part from damage to mitochondrial DNA, and in part due to epigenetic changes that impair the operation of mitochondria and mitochondrial quality control processes. This dysfunction is particularly impactful in tissues with high energy demands, and the brain is at the top of that list.
Today's open access paper reviews present thought on mitochondrial dysfunction as a contributing (or even central) cause of Alzheimer's disease. While the authors focus on Alzheimer's disease specifically, mitochondrial dysfunction in the aging brain is broadly relevant to all neurodegenerative conditions. If it is central in any one condition, it is probably central to all. The fastest way to assess whether or not this is the case is to run clinical trials of therapies capable of greatly restoring lost mitochondrial function and observe the results.
In the near term, mitochondrial transplantation is the approach closest to realization that could in principle achieve dramatic improvement in mitochondrial function. Mitochondrial transplantation involves the delivery of large numbers of functional mitochondria harvested from cell cultures. In the context of improving the function of the aging brain, transplanted mitochondria may need to be delivered intrathecally into the cerebrospinal fluid rather than intravenously into the bloodstream, but otherwise the approach is the same. Animal studies suggest that a sizable improvement lasting for at least months is an achievable goal in human patients. The one caveat is that mitochondrial dysfunction in the brain is not just the result of the cellular mechanisms of aging, but also results from a reduced supply of oxygen and nutrients. The cardiovascular system declines with age, and thus improvement to its function may also be needed to realize the full benefits of mitochondrial transplantation into the brain.
Aging and Alzheimer's: the critical role of mitochondrial dysfunction and synaptic alterations
Alzheimer's disease (AD) is a degenerative brain disorder that is characterized by memory loss and the accumulation of two insoluble protein clumps, i.e., amyloid beta (Aβ) plaques and tau neurofibrillary tangles (NFTs). Multiple years of research have indicated that mitochondrial respiratory complex dysfunction has long been associated with the aetiology of neurodegenerative diseases such as AD. The finding of impaired oxygen and glucose transport in the brains of AD patients is the most significant indirect evidence supporting mitochondrial participation in the disease. According to the mitochondrial cascade theory, the other clinical symptoms of AD should be considered side effects, as mitochondrial malfunction is the primary cause in the majority of instances.
Electron microscope scans of the brains of AD patients have revealed altered mitochondrial morphology, including smaller mitochondria, altered and broken cristae, accumulation of osmophilic components, lipofuscin vacuoles, and elongated connected organelles. Numerous studies have been undertaken to evaluate the relationship between alterations in mitochondria (mtDNA) and AD, which have demonstrated that mtDNA levels in the brain cells and cerebrospinal fluid of AD patients have been reduced
Oxidative phosphorylation (OXPHOS) in mitochondria, which serves as the cell's energy source, produces the majority of the adenosine triphosphate (ATP). Neurons are the most ATP-consuming cell type. The primary reason for this is the requirement to maintain the ionic gradients required for ongoing neurotransmission, electrophysiological activity, and transient synaptic plasticity. In addition to being significant sources of free radical generation, defective mitochondria can trigger apoptosis by releasing cytosolic cytochrome C (cyt). Consequently, neuronal damage could result from even a little reduction in mitochondrial function.
The pathogenesis of AD has been explained through several competing and overlapping models, including the amyloid cascade, tau-first, and mitochondrial cascade hypotheses. While the amyloid and tau models emphasize extracellular plaque and cytoskeletal pathology, respectively, accumulating evidence suggests that mitochondrial dysfunction may act as an upstream trigger influencing both Aβ aggregation and tau hyperphosphorylation.
View the full article at FightAging
