Release of proapoptotic factors from the mitochondria leads to cell death, and signaling events appear to occur "upstream" or "downstream" of the mitochondria. This neat organization is challenged by Lakhani et al. (see the Perspective by Adrain and Martin) in an analysis of knockout mice lacking caspase-3 and caspase-7, both thought to be "downstream." Caspase-3 and -7 are activated when clipped by other caspases after they have been stimulated by molecules released from the mitochondria. In the knockout animals, not only was the "downstream" event, apoptosis, inhibited, but "upstream" events, such as loss of the integrity of the mitochondrial membrane and release of apoptotic factors, were also delayed. These unanticipated results may indicate that caspase-3 and caspase-7 act to promote mitochondrial signals that lead to their own activation and raise a "chicken or egg" conundrum regarding the initiation of the mitochondrial death signals.
S. A. Lakhani, A. Masud, K. Kuida, G. A. Porter Jr., C. J. Booth, W. Z. Mehal, I. Inayat, R. A. Flavell, Caspases 3 and 7: Key mediators of mitochondrial events of apoptosis. Science 311, 847-851 (2006). [Abstract] [Full Text]