Endocrine Abstracts

In addition to their role in cellular energy metabolism, mitochondria are now recognised as central players in cell death. Critical to this role is the mitochondrial permeability transition pore (MPTP) whose opening uncouples mitochondria, preventing them from providing for the energy needs of the cell leading to necrotic cell death. MPTP opening is important in the injury to the heart and brain that follows an ischaemic episode such as a heart attack or stroke and agents that inhibit pore opening protect hearts and brains from ischaemia / reperfusion injury. Mitochondria also play a central role in apoptosis through the release of pro-apoptotic proteins contained in the intermembrane space. These include cytochrome c that activates the caspase cascade responsible for the changes to the cell structure and function that occur in apoptosis. Other factors such as apoptosis inducing factor (AIF) and Smac (or Diablo) are also released from mitochondria in response to an apoptotic stimulus. One mechanism by which these proteins are released may be through opening of the MPTP. This causes mitochondrial swelling, rupture of the outer membrane and non-specific release of intermembrane proteins. However, MPTP opening must be transient for apoptosis to occur, otherwise ATP becomes depleted and cells will die by necrosis even though caspase activation and other early changes characteristic of apoptosis will be observed. According to the severity of the insult to the cell, this allows mitochondria to determine not only whether a cell should die, but also the nature of that death. Another mechanism for intermembrane protein release involves selective permeation of the outer mitochondrial membrane through recruitment of protein such as Bax, Bad and Bid. These proteins, either in their own right, or through interaction with outer membrane proteins such as the voltage dependent anion channel (VDAC), induce a channel in the outer membrane.