MITOCHONDRIA-MEDIATED CELL INJURY

Mitochondria have long been known to participate in the process of cel l injury associated with metabolic failure. Only recently, however, ha ve we come to appreciate the role of mitochondria as primary intracell ular 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 homeost asis and cell signaling. Mitochondria are susceptible to damage by oxi dants, electrophiles, and lipophilic cations and weak acids. Chemical- induced mitochondrial dysfunction may be manifested as diverse bioener getic disorders and considerable effort is required to distinguish bet ween mechanisms involving critical mitochondrial targets and those in which mitochondrial dysfunction is secondary and plays only a modulato ry role in cell injury. The following paragraphs review a few importan t 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 alter ed cell cycle control. Greater understanding of the molecular mechanis ms of mitochondrial bioenergetics, ion regulation, and genetics will l ead to numerous additional examples of mitochondria-mediated cell inju ry, revealing important new insight regarding the prediction, preventi on, diagnosis, and treatment of chemical-induced toxic tissue injury. (C) 1997 Society or Toxicology.