A mechanistic view of mitochondrial death decision pores

Autor(es)

J.E. Belizário ^[1] ; J. Alves ^[2] ; J.M. Occhiucci ^[3] ; M. Garay-Malpartida ^[4] ; A. Sesso ^[5]

Afiliação do(s) autor(es)

^[1] Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Farmacologia

^[2] Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Farmacologia

^[3] Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Farmacologia

^[4] Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Farmacologia

^[5] Universidade de São Paulo. Instituto de Medicina Tropical. Laboratório de Imunopatologia

• Tipo de documento: Artigo Científico
• Fonte: Brazilian Journal of Medical and Biological Research; v. 40, n. 8, p. 1011-1024, 2007-04-12.

Resumo

Mitochondria increase their outer and inner membrane permeability to solutes, protons and metabolites in response to a variety of extrinsic and intrinsic signaling events. The maintenance of cellular and intraorganelle ionic homeostasis, particularly for Ca2+, can determine cell survival or death. Mitochondrial death decision is centered on two processes: inner membrane permeabilization, such as that promoted by the mitochondrial permeability transition pore, formed across inner membranes when Ca2+ reaches a critical threshold, and mitochondrial outer membrane permeabilization, in which the pro-apoptotic proteins BID, BAX, and BAK play active roles. Membrane permeabilization leads to the release of apoptogenic proteins: cytochrome c, apoptosis-inducing factor, Smac/Diablo, HtrA2/Omi, and endonuclease G. Cytochrome c initiates the proteolytic activation of caspases, which in turn cleave hundreds of proteins to produce the morphological and biochemical changes of apoptosis. Voltage-dependent anion channel, cyclophilin D, adenine nucleotide translocase, and the pro-apoptotic proteins BID, BAX, and BAK may be part of the molecular composition of membrane pores leading to mitochondrial permeabilization, but this remains a central question to be resolved. Other transporting pores and channels, including the ceramide channel, the mitochondrial apoptosis-induced channel, as well as a non-specific outer membrane rupture may also be potential release pathways for these apoptogenic factors. In this review, we discuss the mechanistic models by which reactive oxygen species and caspases, via structural and conformational changes of membrane lipids and proteins, promote conditions for inner/outer membrane permeabilization, which may be followed by either opening of pores or a rupture of the outer mitochondrial membrane. (AU)

• Processo FAPESP: 01/01000-7 - Análise da expressão de genes e proteínas e da atividade de enzimas caspases em células do músculo esquelético durante a caquexia induzida por tumores malignos e citocinas
• Beneficiário: José Ernesto Belizario
• Modalidade de apoio: Auxílio à Pesquisa - Regular