The role of mitochondrial factors in apoptosis: a Russian roulette with more than one bullet

This review summarises and evaluates the current knowledge concerning the complex role of released mitochondrial proteins in the apoptotic process

G van Loo


Scholarcy highlights

  • Since the pioneering work of Xiaodong Wang, increasing evidence has been provided that mitochondrial constituents are actively involved in the regulation of apoptotic cell death
  • The contribution of mitochondria to apoptosis was described in terms of disruption of the mitochondrial transmembrane potential, which results from an asymmetric distribution of protons on both sides of the inner mitochondrial membrane
  • All types of second mitochondria-derived activator of caspases/direct IAP-binding protein with low pI-deficient primary cells respond normally to a broad range of apoptotic stimuli. These observations suggest the existence of redundant factors compensating for the loss of Smac/ DIABLO, probably Omi/HtrA2, or that Smac/DIABLO has no essential and general role in apoptosis during development. Another mitochondrial factor that shares functional properties with Smac/DIABLO is the serine protease Omi, known as HtrA2.106 Upon apoptosis induction with anti-Fas, TRAIL, staurosporin and UV-irradiation, this protease is released from the intermembrane space of mitochondria and interacts with cytosolic IAP proteins via a similar IAP binding motif as described above.17 ± 21 Omi/HtrA2 was identified as a 49 kDa serine protease, homologous to the bacterial DegP/high temperature requirement A protein, and was suggested to be involved in cellular stress response pathways
  • Originally identified as a protein involved in mitochondrial DNA replication, endonuclease G was recently shown to be released from mitochondria during apoptosis induced with TNF, agonistic anti-Fas antibodies and UV-irradiation and to translocate to the cell nucleus where it is involved in nuclear DNA breakdown
  • Apoptosis Inducing Factor and endonuclease G are both involved in caspaseindependent nuclear DNA disintegration
  • As yet, no mitochondrial function has been described for Smac/ DIABLO
  • Mitochondria possess an autonomic system, viz. an arsenal of innocent essential molecules required for mitochondrial homeostasis that, once released into the cytosol, become deadly weapons that push the balance towards cell death

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