1 The Human Mitochondrion and Pathophysiology of Aging and Age-related Diseases

Abstract

During the past decade, interest has grown rapidly in the possibility that mitochondrial dysfunction has a significant role in the etiology of aging and the age-related diseases (Wallace 1992b). However, the potential importance of the mitochondrion in these processes has not been fully explored due in part to the dominance of the anatomical and Mendelian paradigms in Western medicine. Although these two paradigms have been highly successful in addressing organ-specific symptoms and Mendelian inherited diseases, respectively, they have been relatively unsuccessful in clarifying the etiology of multisystem, age-related disorders. Aging affects a variety of systems, although to different extents in different individuals. Furthermore, in stark contrast to the prediction of Mendelian genetics in which genetic traits are biallelic and thus quantized (+/+, +/−, −/−), age-related symptoms show a gradual decline suggestive of quantitative rather than quantized genetics. These ambiguities might be explained by adding the mitochondrial energetic and genetics paradigms to the existing anatomical and Mendelian paradigms. The mitochondria generate the energy for the body, although different tissues rely on mitochondrial energy to different extents. Moreover, each cell contains hundreds of mitochondria and thousands of mitochondrial DNAs (mtDNAs), with each mtDNA encoding the same 13 proteins that are critical for mitochondrial energy production. The mtDNA also has a very high mutation rate, such that mtDNA mutations accumulate in tissues over time. This results in a stochastic decline in energy output that ultimately falls below the minimal energetic threshold, resulting in cell loss, tissue dysfunction, and symptoms. WHY DO WE HAVE...