Mitochondrial perturbations and lymphocyte apoptosis: A review

Since the morphology and the genome structure of mitochondria remains intact until the late degradation phase of apoptosis, it has been commonly assumed that mitochondria are not involved in the apoptotic process. This notion has apparently been corroborated by the fact that cells lacking mitochondrial DNA (but which continue to contain mitochondria) are fully competent to undergo apoptosis. Recent functional studies, however, indicate that mitochondria undergo a number of major perturbations early during apoptosis. In particular, the disruption of the mitochondrial inner transmembrane potential (ΔΨ(m)) is an invariant feature of apoptosis that becomes manifest once a cell has passed the point-of-no-return of death programming. The ΔΨ(m) collapse is an early feature of apoptosis in the sense that it precedes common signs of apoptosis at the levels of the nucleus (chromatin condensation, oligonucleosomal DNA fragmentation), of the cytoplasm (vacuolization, calcium influx), and of the plasma membrane (exposure of phosphatidylserine residues on the outer membrane leaflet). At the level of the mitochondrion, the ΔΨ(m) collapse entails an immediate shut-down of the mitochondrial RNA and protein synthesis, uncoupling of the respiratory chain, hyperproduction of superoxide anion, and local oxidation of inner membrane cardiolipins. Moreover, it is followed by the release of apoptogenic proteins from the mitochondrial intermembrane space into the cytosol. The mechanism which underlies the pre-apototic ΔΨ(m) disruption is permeability transition (PT), i.e. the opening of regulated pores of the inner mitochondrial membrane. PT appears to be a critical, cordinating event of apoptosis. Induction of PT suffices to trigger apoptosis, whereas its prevention impedes the manifestation of apoptosis. The apoptosis-inhibitory oncoprotein Bcl-2 acts at the level of the mitochondrion to inhibit PT. These findings underline the primordial role of mitochondria in the apoptotic process.