Mitochondria and cell death - Mechanistic aspects and methodological issues

Mitochondria are involved in cell death for reasons that go beyond ATP supp ly. A recent advance has been the discovery that mitochondria contain and r elease proteins that are involved in the apoptotic cascade, like cytochrome c and apoptosis inducing factor. The involvement of mitochondria in cell d eath, and its being cause or consequence, remain issues that are extremely complex to address in situ. The response of mitochondria may critically dep end on the type of stimulus, on its intensity, and on the specific mitochon drial function that has been primarily perturbed. On the other hand, the ou tcome also depends on the integration of mitochondrial responses that canno t be dissected easily. Here, we try to identify the mechanistic aspects of mitochondrial involvement in cell death as can be derived from our current understanding of mitochondrial physiology, with special emphasis on the per meability transition and its consequences (like onset of swelling, cytochro me c release and respiratory inhibition); and to critically evaluate method s that are widely used to monitor mitochondrial function in situ.