Insights into the mitochondrial signaling pathway: what lessons for chemotherapy?
Mitochondria are potent integrators/coordinators of apoptosis signaling pathways. Indeed, under physiological conditions, the initiation of apoptosis leads to the accumulation of second messengers that converge on mitochondria. In response, these organelles undergo a membrane permeabilization, presumably due to the opening of protein channels, culminating in the release of proapoptotic proteins into the cytosol. Under pathological conditions, a failure of mitochondrial membrane permeabilization (MMP) can result in an inhibition of apoptosis and enhanced resistance to chemotherapy. Several non-mutually exclusive mechanisms may account for a defect in the execution or regulation of MMP. These include (i) alterations in gene transcription, (ii) gene mutations resulting in protein inactivation, and (iii) defects of intracellular localization. This may concern structural proteins of the permeability transition pore complex, as well as MMP regulatory proteins, such as Bax/Bcl-2 family members, p53, and cyclophilin D. Analysis of these mechanisms should improve our understanding of the basic function of mitochondria in apoptosis and help elaborate new strategies to correct MMP failure from a therapeutic perspective.
Brenner
Catherine
C
CNRS UPRESA 8087, Université de Versailles/St Quentin, LGBC Buffon, 45 Avenue des Etats-Unis, 78035 Versailles, France. cbrenner@genetique.uvsq.fr
Le Bras
Morgane
M
Kroemer
Guido
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D006801:Humans; D007473:Ion Channels; D008928:Mitochondria / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction
D000970:Antineoplastic Agents; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins