The development of mitochondrial medicine.

Abstract

Primary defects in mitochondrial function are implicated in over 100 diseses, and the list continues to grow. Yet the first mitochondrial defect-a myopathy-was demonstrated only 35 years ago. The field's dramatic expansion reflects growth of knowledge in three areas: (i) characterization of mitochondrial structure and function, (i) euiation of the steps involved in mitochondrial biosynthesis, and (Ni) discovery of specific mitochondrial DNA. Many mitochondrial diseases are accompanied by mutations in this DNA. Inheritance is by maternal t ission. The metabolic defects encompass the electron transport complexes, intermediates of the tricarboxylic acid cycle, and substrate transport. The clinical manifestations are protean, most often involving skeletal muscie and the central nervous system. In addition to being a primary cause of disease, mitochondrial DNA mutations and impaired oxidation have now been found to occur as secondary phenomena in aging as weli as in age-related degenerative diseases such as Parkinson, Alzheimer, and Huntington diseases, amyotrophic lateral sclerosis and cardiomyopathies, atherosclerosis, and diabetes meflitus. Manifestations of both the primary and secondary mitochondrial diseases are thought to result from the production of oxygen free radicals. With increased understanding of the mechanisms underlying the mitochondrial dysfunctions has come the beginnings of therapeutic sttegies, based mostly on the administration of antioxidants, replacement of cofactors, and provision of nutrients. At the present accelerating pace of development of what may be cafled mitochondrial medicine, much more is likely to be achieved within the next few years.In 1959, the first biochemical studies of a cell organelle in humans were undertaken, following observations made at the bedside of a patient with striking symptoms, never before encountered. These clinical observations, first, led to an idea about the origin ofthe symptoms and, second, to studies of the particular organelle: the mitochondrion (1). The pathophysiology of the mitochondria developed gradually over the years as relevant discoveries were made in biochemistry, cell biology, and molecular biology. During the past few years the field mitochondrial medicine has expanded dramatically, in several directions. I here provide a short review concentrating on those aspects most relevant to clinical medicine. In the accompanying review (174), Wallace describes the molecular, biological, and evolutionary implications of mitochondrial diseases.The Birth of Mitochondrial Medicine (1959)(1960)(1961)(1962): Luft DiseaseThe first patient found to have a mitochondrial disease was a 30-year-old woman who developed clinical symptoms at the age of 7. Her dominant symptoms were enormous perspiration combined with markedly increased fluid intake but without polyuria; extremely high caloric intake (above 3000 kcal per day) at a stable body weight of 38 kg and a body height of 159 cm; and general weakness, particularly prominent in her musculature. The do...

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