Mitochondrial Myopathy Stem Cell

At age five a seemingly healthy boy inexplicably began to lose his hearing, which disappeared entirely before he turned 18. In the interim, he was diagnosed as hyperactive and suffered occasional seizures. By the time he was 23, his vision had declined; he had cataracts, glaucoma and progressive deterioration of the retina. Within five years he had experienced severe seizures, and his kidneys had failed. He died at 28 from his kidney disorder and a systemic infection. At the root of his problems was a minute imperfection in his genes-but not in the familiar ones residing in the long, linear strings of chromosomal DNA that populate every cell nucleus. Instead he was killed by an abnormality in tiny circles of lesser known DNA located in his mitochondria, the power plants of cells. Each such circle contains the genetic blueprints for 37 of the molecules mitochondria need to generate energy. Scientists have known since 1963 that mitochondria in animals harbor their own genes, but errors in those genes were not linked to human ailments until 1988. In that year, my laboratory at Emory University traced the origin of a form of young-adult blindness (Leber’s hereditary optic neuropathy) in several families to a small inherited mutation in a mitochondrial gene. At about the same time, Ian J. Holt, Anita E. Harding and John A. Morgan-Hughes of the Institute of Neurology in London connected deletion of relatively large segments of the mitochondrial DNA molecule to progressive muscle disorders. Investigators at Emory and elsewhere have now learned that flaws in mitochondrial DNA cause or contribute to a wide range of disorders, some of which are obscure but potentially catastrophic. Of perhaps more general interest, mutation of this DNA has a hand in at least some, and perhaps many, cases of diabetes and heart failure. Further, a growing body of evidence suggests that injury to genes in mitochondria may play a role in the aging process and in chronic, degenerative illnesses that become common late in life-such as Alzheimer’s disease and various motor disturbances. Mitochondrial DNA has been attracting attention lately on other grounds, too. By comparing the sequences of base pairs (the variable “rungs,” or coding units, on the familiar DNA “ladder” ) in the mitochondrial DNA of different populations across the globe, scientists have gained exciting clues to the evolution and global migrations of anatomically modern humans [see box on pages 28 and 29]. And forensic investigators have found smaller-scale comparisons useful for identifying the remains of soldiers missing in action (and for others long dead) and for determining whether accused criminals are responsible for misdeeds attributed to them [see box on page 26]. Although most biologists paid little attention to mitochondrial DNA until quite recently, mutation of the genetic material in mitochondria might have been predicted to have consequences for human disease. Mitochondria provide about 90 percent of the energy that cells-and thus tissues, organs and the body as a whole-need to function. They generate energy through a complicated process that involves the relay of electrons along a series of protein complexes (collectively known as the respiratory chain). This relay indirectly enables another complex (ATP synthase) to synthesize ATP (adenosine triphosphate), the energy-carrying molecule of cells. Early on, logic suggested that anything able to compromise ATP production severely in mitochondria could harm or even kill cells and so cause tissues to malfunction and symptoms to develop. Indeed, in 1962 Rolf Luft and his coworkers at the Karolinska Institute and the University of Stockholm reported that an impairment in mitochondrial energy production caused a debilitating disorder Eventually it became clear that the tissues and organs most readily affected by cellular energy declines are the central nervous system, followed, in descending order of sensitivity, by heart and skeletal muscle, the kidneys and hormone-producing tissues. Scientists initially sought the explanation for mitochondrial disorders in mutations of nuclear genes, some of which give rise to mitochondrial components. But by the early 1980s, researchers understood that mitochondrial DNA codes for a number of important molecules. It specifies the structure of 13 proteins (chains of amino acids) that become subunits of ATP synthase and the respiratory chain complexes, and it specifies 24 RNA molecules that help to manufacture those subunits in mitochondria. These findings implied that mitochondrial DNA mutations able to disrupt mitochondrial proteins or RNAs could potentially disturb the energy-producing capacity of mitochondria and produce disease-a suspicion that was borne out by the 1988 reports.