Calling for a Closer Examination of Mitochondrial Biochemistry in the Aging Brain
Mitochondrial dysfunction is strongly associated with the progression of aging, and forms of damage to mitochondrial DNA are one of the contributing causes of aging. Here, researchers review what is known of the changes that occur in mitochondrial biochemistry in the aging brain, and call for further work in this area to clarify the many specific uncertainties. Despite these uncertainties, there is more than enough evidence to move forward with attempts to repair mitochondrial DNA damage, as this may well remove the mitochondrial contribution to degenerative aging and age-related disease even in the absence of a complete understanding of all of the processes involved. There is a very reasonable expectation of significant gains to result from this work, justifying greater efforts in this area of development.
The mitochondrion is a ubiquitous intracellular organelle instrumental to eukaryotic existence. It is the major intracellular site of oxygen consumption and producer of the high energy molecule adenosine triphosphate (ATP). Mitochondria carry out tasks besides energy production, including cellular homeostasis and signalling, iron processing, haem and steroid synthesis, protein and lipid biosynthesis and apoptosis. These organelles are extremely dynamic and variable, capable of responding to numerous stimuli (including temperature, nutrients, hormones, exercise and hypoxia); they initiate the production of new mitochondria and their selective removal. The brain, per gram, has the highest demand for glucose than any other tissue. Brain function is entirely dependent on glucose and oxygen from the carotid and vertebral circulation. Glucose oxidation followed by oxidative phosphorylation is accountable for the vast majority of ATP generated in the brain. Brain energy metabolism declines with age. Our own group and others have observed this decline to be clinically homogenous in most brain regions. This metabolic change is considered to be a feature of the ageing phenotype as well as age-related neurodegeneration, where there is mounting evidence supporting the role of dysfunctional mitochondria in their progression.
As our understanding of ageing has progressed mitochondrial function has come to the forefront as pivotal to the aged phenotype. Classical theories, including the mitochondrial free radical theory of ageing (MFRTA), have led the field. According to the MFRTA an accumulation of oxidative damage, caused by mitochondrial free radicals, is the driving force behind ageing. However, this theory conflicts with growing evidence from animal models. Species comparison between the long lived naked mole rat and short lived mouse indicates little difference in the production of ROS between species and no age-dependent variation in antioxidant enzyme expression. This suggests that mitochondrial ROS may act as signalling molecules, prolonging maximum lifespan. MFRTA also fails to fully explain the functional brain mitochondrial deficits that occur with age. These deficits include reduced respiration, dynamic changes in shape and size, activation of permeability transition pore and loss of membrane potential. Although functional studies have gone some way to identifying these mitochondrial changes, there is variability found in the direction and extent to which these differences occur. There is even evidence to suggest that oxidative phosphorylation activity may in fact increase with age. There are similar inconsistencies which exist for the role and the activity of mitochondrial antioxidants, fusion and fission dynamics and other mitochondrial proteins with age. Profiling of mitochondrial protein expression in tissues from different ages can add molecular insight, which in conjunction with functional studies can be a powerful approach towards unravelling this complexity.
With evidence pointing toward a pivotal role of mitochondria in neurodegenerative disease and the aged phenotype, an understanding of the changes to the proteome is warranted. Mitochondrial proteomic alteration in brain ageing is clear, however the directionality and extent of these alterations is not. The application of quantitative proteomics to mitochondria is timely to more comprehensively investigate these changes. With the advent of new proteomic technologies, bringing greater reproducibility and accuracy, the field of mitochondrial proteomics is open-ended and improved clarity of the mitochondrial changes that occur in the brain with age is expected in the near future.