An Analysis of Mitochondrial Dysfunction in Aging and Disease

Every cell has its herd of bacteria-like mitochondria, generating fuel for cellular metabolism but also emitting damaging reactive compounds - largely damaging themselves, in fact. Differences in mitochondrial damage resistance are thought to be an important determinant of differences in species life span. Similarly, accumulated mitochondrial damage is most likely an in important contribution to degenerative aging in individuals - making therapies capable of repair a high priority. Here researchers dig in to the degree to which mitochondrial dysfunction appears in aging and various diseases:

Besides their cardinal role in ATP metabolism mitochondria are the main producers of endogenous oxidative radicals. These highly volatile species react with lipids, proteins and nucleic acids in their vicinity. The mitochondrial theory of aging states that an accumulation of damage to these macromolecules throughout the lifetime of an organism leads to cellular decay, loss of tissue homeostasis, and finally to death. Multiple lines of evidence have corroborated this theory and suggested that mitochondrial maintenance may be important in promoting longevity and healthy aging. Indeed, mitochondria have been implicated in most age related diseases such as neurodegeneration, cardiovascular disease and diabetes.

If mitochondrial dysfunction is causative in aging, we would expect the accelerated aging disorders to exhibit features of mitochondrial disease. To investigate this, we compiled a database of the clinical parameters seen in mitochondrial diseases, Based on this database we developed extensive bioinformatics tools to dissect whether a disease could be characterized as mitochondrial or not. [Using] these tools we identified a number of diseases as mitochondrially associated that had not previously been considered as mitochondrial. Recently a number of [accelerated aging conditions] have been suggested to have mitochondrial dysfunction and these disorders were also identified by our tools.

With the validation of the tools we went on to investigate the mitochondrial involvement in a number of monogenic diseases. Interestingly, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis all showed a substantial mitochondrial involvement. Further, when adding the accelerated aging disorders to the database two groups of progeria appeared; one group associated with chromosomal instability and another group clustered with mitochondrial diseases. Normal aging seemed to associate closer with the mitochondrial group in the clustering algorithm but showed mixed mitochondrial and non-mitochondrial [attributes]. Taken together these findings indicate at least two separate causes of aging, one of them possibly being mitochondrial.



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