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The techniques of human molecular genetics have been rapidly applied to the study of hearing loss. These studies have implicated more than 60 loci as causes of nonsyndromic hearing loss. Mutations at more than a dozen nuclear genes have been demonstrated to cause hearing loss, and these have been covered in recent reviews. However, a perhaps unexpected feature of the molecular characterization of human hearing loss has been the occurrence of mutations in the mitochondrial DNA (mtDNA). The importance of mitochondrial function in hearing is emphasized by the recent discovery of mutations in a nuclear-encoded mitochondrial protein which results in hearing loss. This article reviews the current status of our knowledge of mtDNA mutations that have been shown to cause hearing loss, and the suggestion of potential molecular, cellular and tissue-specific pathophysiological mechanisms by which dysfunction of mitochondria may lead to a loss of hearing. [ABSTRACT FROM AUTHOR]

Mitochondria have long been known to participate in the process of cell injury associated with metabolic failure. Only recently, however, have we come to appreciate the role of mitochondria as primary intracellular targets in the initiation of cell dysfunction. In addition to ATP synthesis, mitochondria are also critical to modulation of cell redox status, osmotic regulation, pH control, and cytosolic calcium homeostasis and cell signaling. Mitochondria are susceptible to damage by oxidants, electrophiles, and lipophilic cations and weak acids. Chemical-induced mitochondrial dysfunction may be manifested as diverse bioenergetic disorders and considerable effort is required to distinguish between mechanisms involving critical mitochondrial targets and those in which mitochondrial dysfunction is secondary and plays only a modulatory role in cell injury. The following paragraphs review a few important examples of chemical-induced cytotoxic responses that are manifested as interference with mitochondrial metabolism and bioenergetics, gene regulation, or signal transduction in the form of apoptosis and altered cell cycle control. Greater understanding of the molecular mechanisms of mitochondrial bioenergetics, ion regulation, and genetics will lead to numerous additional examples of mitochondria-mediated cell injury, revealing important new insight regarding the prediction, prevention, diagnosis, and treatment of chemical-induced toxic tissue injury. [ABSTRACT FROM AUTHOR]

The vestibular and ototoxic effects of the aminoglycoside antibiotics (streptomycin, gentamycin, kanamycin, tobramycin, neomycin) are well known; streptomycin, in particular, has been found to cause irreversible, profound, high frequency sensorineural deafness in hypersensitive persons. Aminoglycoside ototoxicity occurs both sporadically and within families and has been associated with a mitochondrial DNA (mtDNA) 1555A to G point mutation in the 12S ribosomal RNA gene. We report on the molecular analysis of a South African family with streptomycin induced sensorineural deafness in which we have found transmission of this same predisposing mutation. It is now possible to identify people who are at risk of hearing loss if treated with aminoglycosides in the future and to counsel them accordingly. In view of the fact that aminoglycoside antibiotics remain in widespread use for the treatment of infections, in particular for tuberculosis, which is currently of epidemic proportions in South Africa, this finding has important implications for the family concerned. In addition, other South African families may potentially be at risk if they carry the same mutation. [ABSTRACT FROM PUBLISHER]